The SWI/SNF complex and cancer
D Reisman1, S Glaros1and EA Thompson2
1Department of Internal Medicine, University of Michigan College of Medicine, Ann Arbor, MI, USA and2Department of Cancer
Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, USA
The mammalian SWI/SNF complexes mediate ATP-
dependent chromatin remodeling processes that are critical
for differentiation and proliferation. Not surprisingly, loss
of SWI/SNF function has been associated with malignant
transformation, and a substantial body of evidence
indicates that several components of the SWI/SNF
complexes function as tumor suppressors. This review
summarizes the evidence that underlies this conclusion,
with particular emphasis upon the two catalytic subunits of
the SWI/SNF complexes, BRM, the mammalian ortholog
of SWI2/SNF2 in yeast and brahma in Drosophila, and
Brahma-related gene-1 (BRG1).
Oncogene (2009) 28, 1653–1668; doi:10.1038/onc.2009.4;
published online 23 February 2009
Keywords: BRG1; BRM; BAF47; tumor suppressor;
The SWI/SNF chromatin-remodeling complex plays
essential roles in a variety of cellular processes including
differentiation, proliferation and DNA repair. Loss of
SWI/SNF subunits has been reported in a number of
malignant cell lines and tumors, and a large number of
experimental observations suggest that this complex
functions as a tumor suppressor. In this review, we
describe the characterization of this gene family and
what is known about its many functions, with a focus on
possible roles of SWI/SNF in cancer development,
progression and therapy.
Characterization of the SWI/SNF family of genes
The components of the SWI/SNF chromatin-remodeling
complex were initially identified in screens for genes that
regulate mating-type switching (SWI) and sucrose non-
fermenting (SNF) phenotypes in yeasts (Carlson et al.,
1981; Neigeborn and Carlson, 1984, 1987; Stern et al.,
1984; Abrams et al., 1986; Nasmyth and Shore, 1987;
Carlson and Laurent, 1994). It was recognized that a
subset of the SWI genes are identical to those identified in
the SNF screen, and those genes that are involved both in
mating-type switching and sucrose fermentation have
come to be known as SWI/SNF genes (Peterson et al.,
1994; Wolffe, 1994). Although SWI/SNF is a relatively
rare enzyme in yeast, present at only 100–500 copies per
nucleus (Cote et al., 1994), it has been estimated that
5–7% of all yeast genes require SWI/SNF activity for
expression (Sudarsanam et al., 2000; Zraly et al., 2006;
Monahan et al., 2008). Estimates of the role of SWI/SNF
in the control of Drosophila gene expression range from
1–2% of the genome (based upon inactivation of SNR1/
SNF5) to essentially the whole genome (based upon
estimated chromosomal loss of RNA polymerase II in
cells that express a dominant-negative brahma allele)
(Armstrong et al., 2002). In yeast, the SWI/SNF complex
can both promote and suppress gene expression (Zhang
et al., 2007); about a third of the yeast genes regulated by
SWI/SNF are suppressed (Sudarsanam et al., 2000).
The role of SWI/SNF genes in the differentiation of
multicellular organisms was initially demonstrated by
characterization of the Drosophila homeotic gene brahma
or BRM (Tamkun, 1995). This gene was identified in
screens for dominant suppressors of Polycomb mutations
(Tamkun et al., 1992). BRM is also a transcriptional
activator of Hox genes and therefore required for the
specification of body segment identities (Armstrong et al.,
2002). Sequence analysis established that BRM is a
member of the Drosophila trithorax gene group and thus
likely to be involved in chromatin remodeling, and BRM
is homologous to yeast SWI2/SNF2 (Tamkun, 1995;
Papoulas et al., 1998). The Drosophila BRM amino
sequence is 56% identical and 72% similar to the human
BRM protein (Elfring et al., 1994).
Drosophila BRM-containing complexes bind the
trithorax group Zeste to activate nucleosomal templates
(Kal et al., 2000). Three other Drosophila trithorax genes
have been identified as SWI/SNF homologs, which, in
Drosophila, are known as BRM-associated proteins or
BAPs: SNR1/BAP45 is homologous to the mammalian
BAF47 and to yeast SNF5 (Dingwall et al., 1995); Osa is
homologous to the mammalian BAF250 and to yeast
SWI1 (Collins et al., 1999; Nie et al., 2000); and Moira/
BAP155 is homologous to the mammalian BAF155/
BAF170 and to the yeast SWI3 (Neely and Workman,
2002) (Table 1). Elucidation of the role of these genes in
pattern formation established a functional link between
SWI/SNF activity and development in multicellular
Received 26 September 2008; revised 1 December 2008; accepted 22
January 2009; published online 23 February 2009
Correspondence: Dr D Reisman, Division of Hematology/Oncology,
Department of Internal Medicine, B-570B MSRBII, Campus Box
0686, 1150 W Medical Center Drive, Ann Arbor, MI 48109-0686,
Oncogene (2009) 28, 1653–1668
& 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00
Composition of the SWI/SNF complexes
Mammalian cells express BRM as well as a closely
related protein called Brahma-related gene-1 (BRG1).
Human BRG1 is approximately 74% identical to
human BRM (Khavari et al., 1993), 52% identical to
Drosophila BRM and 33% identical to yeast SWI2/
SNF2 (Fry and Peterson, 2001). The mammalian SWI/
SNF complexes contain, in addition to BRM or BRG1,
8–10 subunits, which are referred to as BRM- or BRG1-
associated factors or BAFs (Wang et al., 1996a,b).
Table 1 lists all of the well-characterized mammalian
BAFs and shows their non-vertebrate orthologs, the
Drosophila BAPs and yeast SWI/SNF gene family
members. Two features of Table 1 warrant emphasis.
First, no single mammalian SWI/SNF complex will
contain all of these subunits; and second, not all
mammalian SWI/SNF subunits have invertebrate ortho-
logs, suggesting that the mammalian SWI/SNF com-
plexes are structurally and, perhaps functionally, more
diverse than those of yeast or flies. The yeast SWI/SNF
complex exhibits an apparent molecular mass of
1.14MDa (Smith et al., 2003), whereas the mammalian
SWI/SNF complex has an apparent molecular mass of
E2MDa. The stoichiometry of the SWI/SNF com-
plexes has not been unambiguously resolved, but it is
most likely that no single complex contains all of the
subunits listed in Table 1. Mammalian BAF proteins are
conventionally identified by their molecular size; hence
BAF47 refers to a BRG1-associated protein with an
apparent molecular mass of 47kDa. BAF47 has been
shown to be homologous to both SNF5 in yeast and
SNR1 in Drosophila. In parallel, BAF47 was cloned as a
gene that is required for lentiviral integration and was
thus originally referred to as INI1 (Kalpana et al., 1994).
It is believed that an individual SWI/SNF complex
contains either BRM or BRG1, but not both (Wang
et al., 1996a,b), such that BRM/BAF complexes
are structurally distinct from BRG1/BAF complexes
(Figure 1). The extent to which these complexes are
functionally distinct is a topic of active investigation.
The BRG1-containing complexes are further divided
into those that contain the BAF250 (or OSA protein) or
the BAF180 protein (Wang, 2003), which is thought to
be a fusion protein of three separate RSC yeast proteins
(Xue et al., 2000). BAF180 is the mammalian ortholog
of Drosophila polybromo (Table 1), and the polybromo-
containing SWI/SNF complex has been designated as
PBAF, to distinguish it from the BAF250-containing
BRM/BAF and BRG1/BAF complexes (Figure 1).
Several other complexes have been identified that
contain BRG1 and a subset of SWI/SNF factors. These
complexes include the WINAC complex, which contains
the Williams syndrome transcription factor plus pro-
teins involved in DNA replication and transcriptional
elongation (Aoyagi, 2005 #3; Kitagawa, 2003 #1), the
NUMAC complex, which contains coactivator-asso-
ciated arginine methyltransferase 1 (Xu, 2004 #801), and
two repressor complexes that collaborate with Kap1 or
mSin3A (Underhill, 2000 #7) to recruit histone deace-
tylases (for review see Trotter and Archer (2008)).
Recently, a new complex has been discovered; it is in low
abundance and contains an extra subunit, ENL,
that was conserved between human and yeast SWI/
SNF (Nie et al., 2003). Interestingly, ENL is a fusion
BRM. Each of these proteins contain an Rb binding, ATPase and
Bromo domains. Despite these similarities, BRG1 and BRM are
only 75% similar at the proteins. BRM differs as it has a poly q
section that codes B33 repeating glutamine residues.
The different domains that are contained in BRG1 and
Table 1The different components in the yeast, Drosophila and
mammalian SWI/SNF complex
Mammalian SWI/SNF subunits Non-vertebrate orthologs
Although some components are conserved across species, others can
only uniquely be found in the higher order mammalian species.
SWI/SNF and cancer
D Reisman et al
partner for the gene product of the MLL gene, which is
a common target for chromosomal translocations in
human acute leukemia. This MLL-ENL fusion protein
associates and cooperates with SWI/SNF complexes to
activate transcription of the promoter of HoxA7, a
downstream target essential for the oncogenic activity of
SWI/SNF functions as an ATP-dependent
Genetic screens for SWI/SNF suppressor mutants
identified several mutations in histones and other
chromatin-related proteins, suggesting that the SWI/
SNF complex may act at the level of the chromatin
(Kruger et al., 1995; Bortvin and Winston, 1996).
A number of elegant biochemical studies have been
carried out to define the functions of SWI/SNF proteins
in yeast and multicellular organisms (Hirschhorn et al.,
1992; Kwon et al., 1994; Peterson and Tamkun, 1995;
Tamkun, 1995; Peterson, 1998). These analyses revealed
that the SWI/SNF proteins function as ATP-dependent
chromatin-remodeling complexes. Several models have
been proposed to account for the ability of SWI/SNF to
modify chromatin structure (Peterson and Workman,
2000; Hassan et al., 2001). Alternative models include
ATP-dependent movement of histone octamers in
cis along the DNA, transfer of histone octamers from
one nucleosomal array to another or replacement of
nucleosomal histones (Smith and Peterson, 2005;
Saha et al., 2006). Further studies revealed that
nucleosome remodeling by the yeast SWI/SNF is bi-
directional along the DNA, resulting in a continuous
positional re-distribution around a characteristic dis-
tance of motion of approximately 28bp (Shundrovsky
et al., 2006). The net result is an altered structure that
is hypersensitive to nuclease digestion and exhibits
increased affinity for transcription factors (Schnitzler
et al., 1998) and basal transcriptional machinery,
such as the TATA box-binding protein, TBP (Imbal-
zano et al., 1994). Such observations inform the
prevailing view that SWI/SNF complexes regulate gene
expression, at least in part, by inducing a nucleosome
conformation that is more accessible to the transcrip-
The energy for SWI/SNF-mediated chromatin remo-
deling is transduced by the catalytic subunit, BRM or
BRG1, both of which have DNA-dependent ATPase
activity (Muchardt and Yaniv, 1999a; Hassan et al.,
2001). It was initially assumed that the intact SWI/SNF
complex was required for chromatin remodeling. How-
ever, this assumption has been challenged by the
observation that both BRG1 and BRM have remodeling
activity in the absence of other subunits (Phelan et al.,
1999). Addition of other core subunits, such as BAF47,
BAF155 and BAF170, increases remodeling activity to a
level comparable with that of the whole SWI/SNF
complex, indicating that the entire complex is not
absolutely necessary for chromatin remodeling, at least
Mammalian BRM and BRG1 share approximately
75% identity at the amino-acid level. The first 60 amino
acids of BRG1 and BRM are divergent. BRM contains
a polyQ expansion repeat that encodes approximately
33 glutamines (216–254aa), whereas BRG1 contains no
such repeat (Figure 2). The length of the BRM polyQ
repeat varies among cell lines, but it is not known if
the expansion of this repeat affects BRM function
(Muchardt and Yaniv, 1993). There are six conserved
domains in BRM and BRG1: QLQ domain, a proline-
rich domain, a small helicase/SANT-associated domain,
a DNA-dependent ATPase domain, an RB-binding
domain (LxCxE) and a Bromo domain. The carboxy-
terminal Bromo domain [BRG1 (1455–1575); BRM
(1380–1500)] binds acetylated histones (Winston and
Allis, 1999) and is necessary for the stable association of
the SWI/SNF complex with chromatin in vitro (Martens
and Winston, 2003). This binding, in conjunction with
adherence to transcription factors, is thought to be how
SWI/SNF identifies the chromatin segment with which it
will associate and subsequently elicit gene expression.
BRM and BRG1 also contain an LxCxE motif
[BRG1: LTCEE (1356aa); BRM: LTCEE (1292aa)]
that is essential for binding to members of the RB tumor
suppressor family (Dahiya et al., 2000). Other regions
within BRG1 and BRM are also believed to facilitate
RB family binding (Bourachot et al., 1999; Dahiya et al.,
2000). The ATPase domains of BRM and BRG1 are
composed of helicase and DEAD box domains, which
function as the motor units that convert ATP energy to
mechanical movement (Muchardt and Yaniv, 1999a).
These regions are highly conserved and show a high
homology with both DEAD box proteins and helicase
domain in other species (Chiba et al., 1994). Both BRG1
(210–345aa) and BRM (255–375aa) are highly enriched
for proline residues, 35 and 21%, respectively, near their
N termini. The proline-rich region in BRM is just distal
to the polyQ region, which is not contained in BRG1.
Both BRM and BRG1 contain B50aa helicase/SANT-
associated domains [BRG1 (475–525); BRM (450–500)],
which are predicted to bind DNA and are often found
associated with helicases. BRG1 (170–200aa) and BRM
(168–208aa) both contain a QLQ domain motif that has
been shown to be involved in protein–protein interactions.
BRM genes that exist. Within BRM and BRG1, additional genes
exist that utilize the last 10–15 exons. The function of these
minigenes is not known. Moreover, both BRG1 and BRM have an
alternatively spliced exon(s). The expression of BRM is further
complicated by having two different transcription start sites.
A complex set of expression pattern of the BRG1 and
SWI/SNF and cancer
D Reisman et al
The BRM and BRG1 genes (SMARCA2 and
SMARCA4, respectively) contain about 35 exons and
are subject to alternative splicing of a single exon near
their C termini (Figure 3). The BRG1 alternatively
spliced exon contains a high proportion of serine
residues and may have some role in phosphorylation-
dependent control of the splice variant that includes this
exon; however, the function of this exon remains
unknown at this time. Alternative promoter utilization
contributes additional regulatory variance to BRM,
which is transcribed from two different promoters
(Figure 3). Both BRM and BRG1 genes have internal
promoters that give rise to carboxy-terminal truncated
proteins (Figure 3). We have cloned and expressed
cDNAs that correspond to the BGR1 C-terminal
fragments (unpublished data), but the function, if any,
of these proteins is unknown.
The SWI/SNF complex functions as a master regulator
of gene expression
SWI/SNF is a master regulator of gene expression.
In mammalian cells, SWI/SNF has been linked to a
large number of transcription factors. The oncogenic
transcription heterodimer activated protein-1 (AP-1) is
known to be SWI/SNF dependent (Ito et al., 2001);
similarly, EKLF, which regulates b-hemogloblin synth-
esis, also requires this complex for its function (Arm-
strong et al., 1998; Lee et al., 1999). All known steroid
receptors are functionally linked to SWI/SNF (Yoshi-
naga et al., 1992; Sumi-Ichinose et al., 1997; Fryer and
Archer, 1998; Belandia et al., 2002; Inoue et al., 2002;
Marshall et al., 2003; Flajollet et al., 2007). SWI/SNF
has been linked to CD44, CEACAM1, E-cadherin and
various integrins (Liu et al., 2001; Hendricks et al., 2004;
Hill et al., 2004). It is tied to the expression of a large
number of interferon (IFN)-inducible genes (Wang
et al., 2005; Yan et al., 2005). SWI/SNF has also been
shown to regulate the expression of an array of genes
such as c-FOS, CSF-1, CRYAB, MIM-1, p21, HSP70,
vimentin, cyclindromatosis and cyclin A (Murphy et al.,
1999; Liu et al., 2001; Yamamichi-Nishina et al., 2003;
Hendricks et al., 2004; Wang et al., 2005). SWI/SNF has
been shown to modulate alternative splicing by creating
(Batsche et al., 2006). Hence, SWI/SNF does not
regulate an exclusive signaling pathway; instead, it
serves as a fundamental component of various essential,
and often unrelated, pathways.
The SWI/SNF complex is involved in differentiation
The SWI/SNF gene family was initially recognized
because of its role in differentiation in yeast (mating-
type switching) and Drosophila (pattern formation).
SWI/SNF has also been strongly linked to mammalian
differentiation. Transforming growth factor-b is a
master regulator of cellular function and differentiation,
and most transforming growth factor-b responses in
human epithelial cells are dependent on BRG1 function
(Xi et al., 2008). In the early developing mouse embryo,
BRG1 is expressed throughout pre-implantation devel-
opment, whereas zygotic BRM is clearly detectable only
when differentiation first occurs, at the blastocyst stage.
BRM is restricted to the inner cell mass, and cell-type-
specific expression of BRM is also observed after
differentiation of embryonic stem cells (LeGouy et al.,
1998). In adult tissue, we found that BRG1 expression is
predominantly seen in cell types that constantly undergo
proliferation or self-renewal, whereas BRM is prefere-
ntially expressed in the brain, liver, fibromuscular stroma
and endothelial cells, cell types not constantly engaged
in proliferation or self-renewal (Reisman et al., 2005).
Muscle development has been linked to the SWI/SNF
complex. Myo-D,a critical
mesenchymal cell differentiation, requires SWI/SNF
activity (de La Serna et al., 2001a,b; Roy et al., 2002).
BRG1 is required by geminin, Ngnr1 and Neuro-D for
neuronal differentiation (Seo et al., 2005a,b). RNAi-
mediated knockdown of BAF60 in embryonic stem cells
inhibits cardiovascular morphogenesis (Lickert et al.,
2004). A dominant-negative BRG1 allele blocks myeloid
differentiation of 32Dcl3 cells (Vradii et al., 2006),
whereas loss of BRG1 in keratinocytes results in defects
in limb patterning (Indra et al., 2005). Studies in
embryonic stem cells have revealed that lack of
BAF250 can compromise cell pluripotency and severely
inhibit self-renewal, whereas functional BAF250 con-
tributes to the proper expression of numerous genes
involved in embryonic stem cell self-renewal, including
Sox2, Utf1 and Oct4 (Yan et al., 2008) (Gao et al.,
2008). Furthermore, pluripotency defects in BAF250a
mutant embryonic stem cells appear to be cell lineage
specific (Gao et al., 2008; Yan et al., 2008). Thus, SWI/
SNF activity appears to be essential for differentiation
in yeasts, flies and mammals. It is therefore not
surprising that SWI/SNF factors are also involved in
malignant transformation, an association most clearly
demonstrated with the SWI/SNF subunit BAF47.
master regulator of
The BAF47 subunit of the SWI/SNF complex
is a bona fide tumor suppressor
INI1 was initially discovered as a protein that binds
HIV integrase (Kalpana et al., 1994) and was later
are complexes that contain either BRG1 or BRM. The BRG1
complexes are further subdivided based upon an additional
subunit: either BAF250 or BAF180. As in lung cancer, when both
BRG1 and BRM are silenced, there can be no SWI/SNF activity as
illustrated in this diagram.
Three major arranges of the SWI/SNF complex. There
SWI/SNF and cancer
D Reisman et al
shown to be identical to the BAF47 component of the
SWI/SNF chromatin-remodeling complex (Wang et al.,
1996a). The gene that encodes BAF47 is located on
chromosome 22q11, a region that is frequently rear-
ranged in pediatric rhabdoid tumors (Versteege et al.,
1998). BAF47 has been reported to undergo hetero-
zygous deletion in both the chronic and acute phase of
CML, suggesting that it plays a role in this cancer
(Grand et al., 1999). Alteration in BAF47 has also been
detected in a small subset (3–4%) of Hodgkin’s
lymphoma patients (Yuge et al., 2000).
The strongest evidence for the role of BAF47 in
cancer development comes from studies on rhabdoid
tumors showing that one BAF47 allele is consistently
deleted, and the other allele is either mutated or silenced
by methylation (Versteege et al., 1998; Rousseau-Merck
et al., 1999; Sevenet et al., 1999a,b; Biegel et al., 2000,
2002; Biegel and Pollack, 2004). These data initially
implicated BAF47 as a tumor suppressor gene. This
hypothesis was subsequently confirmed by the observa-
tion that the heterozygous knockout of BAF47 (Snf5þ/?)
in mice results in tumors that are histologically similar
to human malignant rhabdoid tumors. Roberts et al.
(2002) used a conditional inactivating allele to show that
loss of BAF47 results in lymphomas or rhabdoid tumors
with 100% penetrance within a median time of 10 weeks
from birth, the most tumorigenic mouse model pub-
lished to date. These observations strongly suggest that
BAF47 is a bona fide tumor suppressor. However, loss of
BAF47 appears to be a very rare event in human tumors
(Roberts and Orkin, 2004). Its loss occurs in both
familial and sporadic renal and extra-renal rhabdoid
tumors, as well as in certain central nervous system
tumors (Biegel et al., 2002; Biegel and Pollack, 2004;
Bourdeaut et al., 2007); however, not more than 50
patients have been identified with this defect, and loss of
BAF47 has very infrequently been observed in any adult
tumor (Grand et al., 1999; Manda et al., 2000; Yuge
et al., 2000; DeCristofaro et al., 2001). Instead, in adult
tumors, the major cancer defect in SWI/SNF appears to
be the loss of BRG1, BRM or both (Muchardt and
Yaniv, 2001). This appears to occur between 10 and
20% of a variety of tumor types (Reisman et al., 2003;
Glaros et al., 2007).
SWI/SNF subunits and their role in gene regulation
The SWI/SNF complexes may be subdivided based
upon their subunit composition (Figure 1). The BAF
complexes contain BAF250 subunits, which belong to
the ARID (AT-rich DNA-interacting domain) gene
family. Two different genes encode BAF250 proteins.
BAF250A (also known as OSA1 and p270/ARID1A) is
encoded by ARID1A, whereas BAF250B (OSA2) is
encoded by ARID1B (Hurlstone et al., 2002; Wang
et al., 2004b). In addition to the ARID domains,
BAF250s also contain EHD1 and EHD2 domains,
which map to the C termini and mediate protein binding
(Hurlstone et al., 2002). BAF250A has been linked to
the functions of steroid receptors (Inoue et al., 2002).
ARID1A is located in 1p36.11 (Kozmik et al., 2001), a
region frequently deleted in human cancers (Huang
et al., 2007), and may be involved in cancer develop-
ment. BAF250A is lost in two cell lines, C33a and T47D
(DeCristofaro et al., 2001), and may be deficient in as
many as 30% of renal carcinomas and 10% of breast
carcinomas (Wang et al., 2004a). ARID1A- and
ARID1B-containing SWI/SNF complexes appear to
have antagonistic effects on cell cycle progression, with
ARID1A participating in repression and ARID1B in the
induction of key cell cycle regulators such as c-MYC
(Nagl et al., 2006, 2007).
BAF180 (polybromo, PB1, PBRM1)-containing SWI/
SNF complexes have different properties from those
that contain BAF250 subunits (Nie et al., 2000; Lemon
et al., 2001; Wang et al., 2004c) and are designated
polybromo SWI/SNF complexes or PBAF (Figure 1).
BAF180 harbors a distinctive set of structural motifs,
characteristic of three components of RSC (Xue et al.,
2000), another chromatin-remodeling complex in yeast.
It also contains a Bromo domain that binds to
acetylated histones. The BAF180 gene PBRM1 maps
to chromosome 3p21, a frequent site of loss of
heterozygosity in human tumors; but BAF180 has not
yet been reported to be absent in cancer cells or primary
tumors (Sekine et al., 2005).
BAF200 is also believed to function as part of the
PBAF complex, similar to BAF180 (Yan et al., 2005).
BAF200, like BAF250, is a member of the ARID gene
family and is encoded by ARID2. In addition to the
ARID domain, BAF200 contains multiple LXXLL
motifs (which may mediate protein–protein interaction
between cofactors and nuclear hormone receptors),
proline- and glutamine-rich regions, and two C2H2 Zn
fingers (which may interact with either DNA or
among the regulatory factor X family of proteins (Yan
et al., 2005). Knockdown experiments indicate that
BAF200 and BAF180 are required for PBAF-mediated
transactivation of different sets of promoters (Yan et al.,
BAF60 is a family of three separate proteins located
on different chromosomes: BAF60A, BAF60B and
BAF60C (Wang et al., 1996a,b). Each has one or more
alternative transcripts that add to the complexity of the
SWI/SNF complex. BAF60A has been linked to lung
cancer risk (Gorlov, 2005), binds to p53 and is necessary
for steroid receptor function (Hsiao et al., 2003). Baf60C
is expressed specifically in the heart and somites in the
early mouse embryo (Lickert et al., 2004). Silencing of
this gene using siRNA in mouse embryos causes defects
in heart morphogenesis as well as results in abnormal
cardiac and skeletal muscle differentiation (Lickert
et al., 2004) Moreover, BAF60C plays a critical role in
Notch-dependent transcriptional activation and in turn
appears to be essential for the establishment of LR
asymmetry (Takeuchi et al., 2007). Like other SWI/SNF
subunits, BAF60C has two isoforms, both of which
appear to be enriched in the central nervous system and
also bind to and modulate the transcriptional activity of
SWI/SNF and cancer
D Reisman et al
peroxisome proliferator-activated receptor-g and the
retinoic acid-related orphan receptor-a1 (Debril et al.,
2004). Both receptors have anticancer mechanisms,
suggesting that the loss of the SWI/SNF function during
cancer development may impair the function of these
BAF57 has a single high-mobility group (HMG)
domain that displays nonspecific DNA-binding char-
(KLCC) domain. BAF57 binds to and is required for
both estrogen and androgen receptor function (Belandia
et al., 2002; Link et al., 2005). Preliminary data suggest
that BAF57 may also regulate estrogen receptor
expression (unpublished data), but the expression of
BAF57 in primary tumors has not yet been investigated
and the role of BAF57 in the etiology of ER-negative
breast cancer remains to be determined.
Homozygous BAF155 knockout mice develop to
early implantation stage but undergo rapid degeneration
thereafter (Han et al., 2008). About 20% of BAF155
heterozygous mutant embryos display defects in brain
development, angiogenesis and visceral endoderm devel-
opment in the yolk sac (Han et al., 2008). BAF155 has
been shown to stabilize BAF47, BRG1 and BAF60A by
attenuating their proteosomal degradation (Sohn et al.,
2007). BAF155 may be phosphorylated by Akt,
suggesting that PI3K/Akt signaling may modulate
SWI/SNF function (Foster et al., 2006). Loss of
BAF155 has been reported in a small number of cancer
cell lines (DeCristofaro et al., 2001). Moreover, BAF155
maps to 3p21–23, which is not infrequency loss in
human cancers (Ring et al., 1998).
BAF170 has a significant homology with BAF155
(Wang et al., 1996b), 75% at the nucleotide level and
66% at the protein level. In studies involving more than
100 cell lines, this subunit has not been found to be
missing or altered, so any role in cancer development
thus far has not been shown (DeCristofaro et al., 2001).
However, BAF170 maps to 12q13–15, which is fre-
quently altered in human cancers (Ring et al., 1998).
BAF155 contains von Willebrand factor type A (vWA),
SWIRM and Chromo domains, although the function
of these domains in SWI/SNF activity is not well
understood. BAF170 has been shown to regulate turn-
over of BAF57 (Chen and Archer, 2005).
Several actin-related proteins were initially found to
be constituents of the yeast SWI/SNF complex (Cairns
et al., 1998; Peterson et al., 1998). Mammalian SWI/
SNF complexes contain BAF53A (ACTL6A) and
BAF53B (ACTL6B). In addition to these actin-related
proteins, b-actin has also been found to be associated
with the mammalian SWI/SNF complex (Zhao et al.,
1998). BAF53 binds the p53 tumor suppressor protein
(Lee et al., 2005; Wang et al., 2007), and the over-
expression of an N-terminal truncated mutant of
BAF53A caused cell death (Choi et al., 2001a; Lee
et al., 2005), implying an important role for BAF53 in
cell survival. BAF53A is associated with mitotic
chromosomes during mitosis and contributes to the
internal meshwork interactions of the chromatin fiber
(Lee et al., 2007a,b). BAF53 has also been reported to
a kinesin-like coiled-coil
shuttle between the cytoplasm and nucleus (Lee et al.,
2003). BAF53A has also been shown to bind to c-MYC
and is critical for c-MYC oncogenic activity (Lee et al.,
The SWI/SNF ATPase subunit genes are frequently
silenced in cancer
The discovery that BAF47 is a bona fide tumor
suppressor gene suggests that other SWI/SNF subunits
might also be tumor suppressors. We and others have
examined a large number of human tumor-derived cell
lines and primary tumors to determine the extent to
which loss of SWI/SNF proteins occurs during trans-
formation (DeCristofaro et al., 2001) (Muchardt and
Yaniv, 2001). Our laboratory examined a number of
lung cancer and other cancer cell lines for the expression
of the various SWI/SNF subunits (DeCristofaro et al.,
2001; Reisman et al., 2002). We found that BRG1 and
BRM expressions are coordinately lost in about 30–40%
of lung cancer cell lines. Intriguingly, loss of either
BRG1 or BRM was observed at a much lower frequency
than loss of both ATPases. But both BRG1 and BRM
are concomitantly lost in about 15–20% of primary non-
small-cell lung cancers (Reisman et al., 2003; Fukuoka
et al., 2004). Analysis of more than 100 cell lines
revealed that both BRG1 and BRM are lost in about
10% of established tumor cell lines (DeCristofaro et al.,
2001). Immunohistochemical staining of tissue micro-
array samples has shown that BRG1 or BRM is lost in
10–20% of the bladder, colon, breast, melanoma,
esophageal, head/neck, pancreas and ovarian cancers
(Glaros et al., 2007 and unpublished data). These data
suggest that silencing of the SWI/SNF ATPases is
involved in the etiology of a significant number and
diversity of tumors.
Loss of heterozygosity occurs at the BRG1 and BRM loci
BRG1 is located in or near several microsatellite
markers that demonstrate loss of heterozygosity in
human cancers (Medina et al., 2004; Gunduz et al.,
2005), and the BRM locus is a site of loss of
heterozygosity in human cancers as well (Eiriksdottir
et al., 1995; Neville et al., 1995; An et al., 1999; Jin et al.,
1999; Sarkar et al., 2002; Tripathi et al., 2003; Sabah
et al., 2005). About 26% of small-cell lung cancer cell
lines and 76% of non-small-cell lung cancer cell lines
have loss of heterozygosity at D9S288, which is in
proximity to the BRM gene (Girard et al., 2000).
Another satellite marker, D19S221, is near the BRG1
gene, and 23% of small-cell lung cancer cell lines and
77% of non-small-cell lung cancer cell lines exhibit loss
of heterozygosity at this marker (Girard et al., 2000).
Loss of heterozygosity is a hallmark of tumor suppres-
sors, and the observation that both BRM and BRG1
loci exhibit loss of heterozygosity is consistent with the
hypotheses that these two proteins function as tumor
SWI/SNF and cancer
D Reisman et al
BRG1 is silenced by a number of mechanisms
Wong et al. (2000) sequenced BRG1 exons from B180
cell lines, of which 18 cell lines were found to harbor
mutations in BRG1-coding sequences. However, most of
the mutations were heterozygous or were missense
mutations and did not appreciably affect BRG1 expres-
sion. Similarly, Medina et al. (2008) detected mutations
in 24% of lung cancer cell lines. Interestingly, this group
also examined primary lung tumors with loss of
heterozygosity in the BRG1 locus and did not find any
appreciable mutations in these tumors (Medina et al.,
2004). Sentani et al. (2001) found no BRG1 mutations in
8 gastric carcinoma cell lines and 33 primary gastric
carcinomas. Likewise, Valdman et al. (2003) reported no
somatic mutations in any of the 35 BRG1 exons in
samples from 21 prostate cancer patients. Gunduz et al.
(2005), who examined loss of heterozygosity at the 19p13
region in 39 oral cancers using six microsatellite markers,
found allelic deletion in 25 of 39 (64%) samples;
however, they did not find any mutations in either the
BRG1 genomic DNA or mRNA. Although mutations in
BRG1 have been detected in a variety of established
cancer cell lines, such mutations have not been detected
in primary tumors. As only genomic DNA has been
analysed from primary tumors, other mechanisms, such
as epigenetic, protein stability or translational block,
probably underlie the loss of BRG1 in primary tumors.
Further research will be needed to clarify this issue.
BRM is silenced by epigenetic mechanisms
Sequence analysis of BRM from 10 BRM-deficient cell
lines did not reveal any mutations or other alterations
that could explain why BRM is silenced (Glaros et al.,
2007). Unlike BRG1, experimental analysis by various
groups has revealed that BRM is epigenetically silenced
in 17 out of the 17 cell lines examined (Mizutani et al.,
2002; Bourachot et al., 2003; Yamamichi et al., 2005;
Glaros et al., 2007). The observation that BRM is
epigenetically silenced in cancer, rather than mutated,
suggests that it might be possible to restore BRM
function in tumor cells. Given that BRM is lost in
B20% of a broad range of human cancers (Glaros
et al., 2007), and that the introduction of BRM into
BRM-deficient cell lines causes growth arrest (Muchardt
et al., 1998; Muchardt and Yaniv, 1999b; Bourachot
et al., 2003), it is plausible that restoration of BRM
expression might be clinically desirable. Several groups,
including our own, have observed that histone deacety-
lase (HDAC) inhibitors can restore BRM mRNA and
protein expression in a variety of BRM null cell lines
(Mizutani et al., 2002; Bourachot et al., 2003; Yama-
michi et al., 2005; Glaros et al., 2007). Nuclear run-on
transcription assays were used by Yamamichi et al.
(2005) to show that BRM is strongly suppressed at the
post-transcriptional level and that this suppression
could be reversed by HDAC inhibitor treatment.
that BRM overexpression inhibits the growth of
K-Ras-transformed fibroblasts and that introducing
HDAC inhibitors blocks this inhibitory effect of
BRM. There are two carboxy-terminal acetylation sites
in the BRM protein, and after the application of HDAC
inhibitors, they found that the resulting acetylation of
theses site abrogated the function of BRM (Bourachot
et al., 2003). Changing these sites so that they were non-
acetylatable blocked the inactivation of BRM by HDAC
inhibitors. Thus, nonspecific HDAC inhibitors, such as
trichostatin A, butyrate and SAHA, effectively de-
repress BRM expression but result in the accumulation
of inactive, acetylated BRM (Bourachot et al., 2003;
Glaros et al., 2007), which does not restore BRM
function. There is a great deal of interest in the
development of specific HDAC inhibitors, and it is
possible that different HDACs may be involved in
epigenetic silencing of the BRM gene and de-acetylation
of the BRM protein. If this proves to be the case, then it
may be possible to use specific HDAC inhibitors to
induce active BRM in tumor cells.
Transgenic knockout of BRM or BRG1 enhances
Transgenic knockout mouse models have been invalu-
able in pre-clinical investigation of the role of SWI/SNF
in transformation. As cited above, the BAF47 knockout
mouse is the most tumorigenic model reported to date
(Roberts et al., 2002). Knockout experiments with
BRG1 and BRM have revealed that loss of either
ATPase can potentiate cancer development in mice
(Reyes et al., 1998; Bultman et al., 2000, 2008; Glaros
et al., 2008). However, interpretation of the results of
these experiments is complicated by the possibility that
BRG1 and BRM can potentially compensate for each
other in certain circumstances. For example, in BRM
null mice, the expression level of BRG1 is threefold
higher than in wild-type BRM mice (Reyes et al., 1998).
Embryonic fibroblasts from BRM knockout mice
demonstrate striking abnormalities in cell cycle control,
and BRM null mice are larger than wild-type littermates
(Reyes et al., 1998; Muchardt and Yaniv, 1999b; Coisy-
Quivy et al., 2006). These data indicate that loss of
BRM, although non-transforming, disrupts normal cell
cycle control in a manner that cannot entirely be
compensated for by BRG1 overexpression. In this
respect, BRM null mice are primed to undergo
transformation, and we have reported that BRM
knockout mice contain about 10 times more lung
tumors than wild-type mice when tumors are induced
by the lung carcinogen urethane (Glaros et al., 2007).
Knockout of a single allele of BRG1 results in
spontaneous tumor development in about 10% of
BRG1þ/?mice within a year (Bultman et al., 2000,
2008). These tumors originated from the milk line and
stained for histopathology markers indicative of mam-
mary tumors. Interestingly, no alterations were noted in
the remaining BRG1 allele, suggesting that these tumors
arose as a result of haplo-insufficiency. In addition, the
absence of BRM did not change the overall penetrance
SWI/SNF and cancer
D Reisman et al
of the Brg1þ/?tumor phenotype but may have changed
the types of tumor that occur. Biallelic knockout of
BRG1 is embryonically lethal (Sumi-Ichinose et al.,
1997) (Bultman et al., 2000), and until recently it has
been impossible to determine the effects of BRG1
silencing in tumorigenesis. We have now developed a
novel mouse model that permits conditional biallelic
knockout of BRG1 in lung epithelial cells (Glaros et al.,
2008). Our data indicate that the loss of both BRG1
alleles induces apoptosis in non-transformed lung
epithelial cells. BRG1 is required for the establishment
and maintenance of epithelial polarity (Indra et al.,
2005), an observation that is consistent with both the
pro-apoptotic effects of BRG1 knockout in the lung as
well as with the early embryonic lethality of BRG1
knockout in mice. On the other hand, knockout of both
BRG1 alleles in urethane-induced tumors promotes
tumorigenesis (Glaros et al., 2008). BRG1-null, ur-
ethane-induced lung tumors are more abundant, larger
and have a higher index of proliferation than BRG1-
positive tumors, demonstrating that the loss of BRG1
promotes tumorigenesis. Urethane is known to induce
K-Ras mutations, and it is possible that loss of BRG1 in
cells with oncogenic K-Ras mutations promotes tumor
development, whereas loss of BRG1 in cells with wild-
type K-Ras promotes apoptosis. However, this hypoth-
esis remains to be tested.
The phenotypes of BRM?/?, BRG1?/?and BAF47?/?
mice are strikingly different, indicating that there is
much to learn about SWI/SNF function in both normal
development and transformation. Our data on lung
carcinogenesis in transgenic mice suggest that BRM and
BRG1 may be involved in different stages of carcino-
genesis (initiation versus progression) (Glaros et al.,
2008). The unresolved question is the effect of silencing
or mutating the genes that encode both of the catalytic
SWI/SNF subunits. Loss of both BRM and BRG1
occurs with significant frequency in many different types
of solid tumors, and in lung cancer, loss of both subunits
is more common than loss of either, alone (Reisman
et al., 2003; Fukuoka et al., 2004). As noted above,
BAF47 knockout is the most tumorigenic defect that has
been engineered to date. However, SWI/SNF activity is
maintained at some level even in the absence of BAF47
(Doan et al., 2004), which seems to function more as an
enhancer of remodeling activity, rather than an ob-
ligatory component of the chromatin-remodeling com-
plex (Phelan et al., 1999). Conversely, concomitant loss
of both BRG1 and BRM should result in the complete
loss of SWI/SNF-mediated ATP-dependent chromatin-
remodeling activity, with attendant degradation of the
several tumor suppressor functions that require SWI/
SNF. Presumably, therefore, cells that have lost both
BRM and BRG1 should be highly tumorigenic.
BRM and BRG1 play critical roles in the control
of cell proliferation
A large number of tumor cells have lost both BRM and
BRG1 expression (Wong et al., 2000; DeCristofaro et al.,
2001; Glaros et al., 2007) and re-expression of either
BRG1 or BRM inhibits growth of such cells in culture
(Khavari et al., 1993; Muchardt et al., 1998). The growth
inhibitory effects of BRG1 are attenuated by the
adenovirus E1A protein, which blocks the cell cycle
checkpoint functions of RB family members RB1, p107
and p130. The observation that E1A blocks BRG1-
mediated growth inhibition strongly suggests that SWI/
SNF activity is required for normal growth regulation by
RB family members (Dunaief et al., 1994; Strober et al.,
1996), and BRG1 and BRM contain the RB-binding
motif LxCxE and bind RB (Dahiya et al., 2000) as well as
RB family members p107 and p130 (Dunaief et al., 1994;
Strober et al., 1996; Dahiya et al., 2000). Constitutively
active RB does not induce G1 arrest in cells that lack
BRG1 and BRM expression (Strobeck et al., 2000, 2001,
2002; Zhang et al., 2000; Reisman et al., 2002). However,
restoration of BRG1 or BRM expression reconstitutes RB
growth inhibition in such cells.
SWI/SNF is required for E2F-dependent transcrip-
tion (Trouche et al., 1997; Kang et al., 2004; Liu et al.,
2004), although all of the effects of SWI/SNF on RB
checkpoint control may not require binding of BRM or
BRG1 to RB. For example, re-expression of BRG1
induces p21, which inhibits RB phosphorylation by
cyclin dependent kinases (CDKs) (Kang et al., 2004).
Cyclin E has been shown to bind and, in conjunction
with CDK2, phosphorylate BRG1 and BAF155 (Sha-
nahan et al., 1999; Brumby et al., 2002). This observa-
tion raises the interesting possibility that not only does
SWI/SNF regulate the cell cycle checkpoint apparatus
(through RB), but also the cell cycle control machinery
(through cyclin E/CDK2) may feed back to modulate
The p53 tumor suppressor has also been functionally
linked to SWI/SNF (Lee et al., 2002; Wang et al., 2007).
p53 binds BAF53, and SWI/SNF activity is necessary
for p53-mediated transcription activation and p53-
mediated cell cycle control (Bochar et al., 2000; Wang
et al., 2007). It has been reported that p53-mediated cell
cycle arrest is dependent upon the RB family member
p130 (Claudio et al., 2000; Gao et al., 2002; Kapic et al.,
2006), which is known to bind BRG1 and BRM, and, by
analogy with RB1, is likely to require SWI/SNF activity
for function. Thus, the role of SWI/SNF in p53-
mediated checkpoint control is likely to involve both
p53 itself as well as downstream effectors of p53
signaling such as p130. Irrespective of the mechanism,
it is clear that loss of SWI/SNF activity, by silencing
BRM and BRG1, induces a phenocopy of a p53 loss-of-
BRM and BRG1 are linked to DNA repair
SWI/SNF complex plays an important role in DNA
repair (Wuebbles and Jones, 2004; Morrison and Shen,
2006; Menoni et al., 2007; Osley et al., 2007). DNA
repair proteins such as p53, BRCA1 and Fanconi
anemia proteins associate with the SWI/SNF complex
and are functionally dependent on it (Bochar et al.,
SWI/SNF and cancer
D Reisman et al
2000; Otsuki et al., 2001; Lee et al., 2002; Wang et al.,
2007). BRCA1 binds BRG1, and p53-mediated stimula-
tion of transcription by BRCA1 is dependent on BRG1
(Bochar et al., 2000). BAF47-deficient cells are hyper-
sensitive to genotoxic stress (Klochendler-Yeivin et al.,
2006), and re-expression of BRG1 in BRG1-deficient
SW13 cells renders the cells resistant to ultraviolet-
induced DNA damage (Gong et al., 2008). SWI/SNF
facilitates the repair of cyclobutane pyrimidine dimers
(Gaillard et al., 2003) and acetylaminofluorene–guanine
adducts (Hara and Sancar, 2002) in a nucleosomal
context. Studies carried out in vivo indicate that SWI/
SNF is recruited to double-strand break sites (Chai
et al., 2005), and the inactivation of the SWI/SNF
complex results in inefficient DNA double-strand break
repair in vivo (Park et al., 2006). These observations
suggest that SWI/SNF activity (or expression of critical
may predict tumor cell susceptible to radiation and
chemotherapy with DNA-damaging agents.
as BRM and BRG1)
BRM and BRG1 control the expression of genes
that are involved in cellular adhesion
When either BRG1 or BRM is restored in BRG1/BRM-
deficient cell lines, cells show an increase in cell volume,
area of attachment, nuclear size and growth arrest (Hill
et al., 2004). Examination of focal adhesions reveals
changes in paxillin distribution, whereas increases in cell
size and shape correlate with the overexpression of two
integrins and the urokinase-type plasminogen activator
receptor (Hill et al., 2004). These findings suggest that
SWI/SNF regulates the expression of cell-adhesion
proteins and cytoskeleton structure changes. The exact
genes underlying these phenomena are not completely
known. However, the cell-adhesion proteins CD44 and
E-cadherin are regulated by SWI/SNF (Banine et al.,
2005). CD44 transcription appears to require SWI/SNF
activity, but the regulation of E-cadherin expression
appears to be more complex and may involve splicing
(Batsche et al., 2006). Our preliminary data indicate that
BRG1 regulates the expression of several genes that are
involved in controlling Rho family GTPase activity
(including RhoGDIA and IQGAP), and that these
proteins may, in combination with CD44 and ERM
family members, affect the stability of adherens junc-
tions. As loss of CD44 and E-cadherin are commonly
associated with transformation of epithelial cells, this
aspect of SWI/SNF function warrants additional
investigation. We and others have carried out prelimin-
ary microarray experiments to identify BRG1-regulated
genes, and our data suggest that SWI/SNF regulates the
expression of a cohort of important cell-adhesion
proteins such as CEACAM1, as well as the extracellular
matrix proteins such as Sparc, MMP1, MMP2, transge-
lin, GALS3BP P8, PODXL, Integrin A5, LGALS1,
Integrin A3, TIMP3 and PLAU (Liu et al., 2001;
Hendricks et al., 2004; Wang et al., 2005). All of these
interactions are known to be involved in tumor
progression, and we anticipate that this aspect of SWI/
SNF function will form an important focus of future
investigations in our laboratory and others.
BRM and BRG1 are required for the activity
of some nuclear receptors
Steroid receptors have been functionally linked to the
SWI/SNF complex (Yoshinaga et al., 1992). In Droso-
phila, SWI/SNF has been shown to regulate hormone-
responsive ecdysone-induced genes (Schwartz et al.,
2004; Zraly et al., 2006). In mammalian cells, the
glucocorticoid receptor has been functionally linked to
the SWI/SNF complex (Muchardt and Yaniv, 1993;
Ostlund Farrants et al., 1997; Trotter and Archer, 2004),
and the re-expression of either BRG1 or BRM is
sufficient to restore glucocorticoid receptor function in
cells that lack both BRG1 and BRM (Glaros et al.,
2007). Although it has not been investigated, the loss of
BRG1 and BRM could very well underlie the resistance
to glucocorticoids in hematopoietic malignancies such
as myeloma, lymphoma and leukemia, as well as in lung
cancer (Choi et al., 2001b; Ko et al., 2004; Pottier et al.,
2007). The estrogen receptor is also functionally linked
to the SWI/SNF complex (Ichinose et al., 1997;
Belandia et al., 2002), and the androgen receptor is also
SWI/SNF dependent (Inoue et al., 2002; Marshall et al.,
2003; Hong et al., 2005; Link et al., 2005; Dai et al.,
2008). We have found that BRG1 and BRM are lost in
human prostate cancer samples, suggesting that a loss of
SWI/SNF function may play a role in the development
of hormone-refractory prostate cancer. It has been
shown that the retinoic acid receptor is also tied to
SWI/SNF (Sumi-Ichinose et al., 1997; Flajollet et al.,
2007), suggesting that the inactivation of SWI/SNF
would make tumor cells refractory to clinical interven-
tion with this reagent. As nuclear receptors are
important regulators of both proliferation and differ-
entiation, the abrogation of the SWI/SNf complex
would block hormone-sensitive pathways and thereby
lead to cancer progression.
BRM and BRG1 play important roles in the immune
SWI/SNF plays an important role in immune responses,
T-cell development and recombination events (Golding
et al., 1999; Agalioti et al., 2000; Kwon et al., 2000;
Spicuglia et al., 2002; Morshead et al., 2003). The SWI/
SNF complexes have been shown to remodel chromatin
in such a way as to drive consecutive developmental
transitions in T cells in response to external stimuli.
Specific inactivation of SWI/SNF complexes in T cells
demonstrates that such complexes are essential for
thymocyte development. SWI/SNF further contributes
to CD4/CD8 T-cell lineage divergence by repressing
CD4 receptor expression while activating the expression
of CD8 (Chi et al., 2002, 2003; Gebuhr et al., 2003).
Variable-diversity-joining (V(D)J) recombination has
also been shown to be mediated by SWI/SNF. BRG1
SWI/SNF and cancer
D Reisman et al
stimulates in vitro recombination of chromatin and is
also bound to regions in the T-cell receptor (TCR) and
immunoglobulin loci that take part in recombination
events (Golding et al., 1999; Kwon et al., 2000; Spicuglia
et al., 2002; Morshead et al., 2003; Patenge et al., 2004).
More recent studies have shown SWI/SNF to be
fundamental to the promoter-directed assembly of
TCR-b (TCRB) genes (Osipovich et al., 2007); SWI/
SNF is recruited to promoters and then facilitates
recombination by exposing segments of genomic DNA
to V(D)J recombinase. The fact that loss of this
chromatin-remodeling complex in thymocytes inacti-
vates recombinase targets at the endogenous TCRB
locus (Osipovich et al., 2007) provides further evidence
for the role of SWI/SNF in recombination.
SWI/SNF also plays an important role in orchestrat-
ing IFN-induced responses. BRG1 regulates the expres-
sion of IFN-b, which is induced upon viral infection of
many cell types, and is essential for innate viral
immunity (Agalioti et al., 2000). Microarray experi-
ments have further revealed that many IFN-inducible
proteins are SWI/SNF dependent (Yan et al., 2005).
BRG1 induces the expression of a subset of IFN-a-
activated genes in HeLa cells (Huang et al., 2002)
(Liu et al., 2002) and has been shown to be required for
IFN-a to inhibit viral replication. Forced expression of
BRG1 in BRM/BRG1-deficient SW13 cells leads to the
upregulation of various IFN-a target genes (Liu et al.,
2002). Finally, yeast two-hybrid studies have shown that
BRG1 binds to signal transducer and activator of
transcription 2 (STAT2), an IFN-a-activated transcrip-
tion factor (Huang et al., 2002). Importantly, the
induction of all of these genes has been shown to be
inhibited when BAF47 is blocked by RNAi interference
(Coisy-Quivy et al., 2006). As a consequence of BAF47
inhibition, cellular response to viral infections and
cellular antiviral activity are significantly inhibited
(Cui et al., 2004). Thus, the tumors that lack a
functional SWI/SNF may be unable to suppress viral
infection and replication. As such, these tumors might
become viral factories, leading to a prolonged cytokine
surge by surrounding normal cells. This may be one
mechanism of tumor-induced cachexia.
Major histocompatibility complex class I and II gene
expression is also regulated by SWI/SNF. IFN-g
induction of CIITA, the master regulator of major
histocompatibility complex class II expression (Mudha-
sani and Fontes, 2002), requires SWI/SNF. In addition,
BRG1 also associates with the activation of the
enhancer A of the major histocompatibility complex
class I promoter (Brockmann et al., 2001). Major
histocompatibility complex class I and II proteins are
essential for immune surveillance, and loss of SWI/SNF
function could conceivably make tumors invisible to the
BRM and BRG1 exhibit partial functional redundancy
Biochemical evidence indicates that BRM and BRG1
nucleate different SWI/SNF/BAF complexes, and data
from transgenic knockout mice indicate that these two
complexes are not entirely redundant in their functions
in vivo. BRG1 knockout mice are embryonically lethal,
whereas BRM mice develop more or less normally.
BRM knockout mice express very low levels of CD44,
even though BRG1 levels are increased threefold in
BRM null mice (Reisman et al., 2002). Paradoxically,
the re-expression of either BRG1 or BRM into BRG1/
BRM-deficient cell lines induces CD44 expression in
culture (Strobeck et al., 2001; Reisman et al., 2002). This
paradox emphasizes the point that one may not be able
to use transient overexpression of individual ATPase
subunits to discriminate between functions that are non-
redundant when BRM or BRG1 is expressed at
physiological levels. Hence caution must be used in
interpreting the results of experiments in which BRG1
or BRM is transiently overexpressed. Additional studies
will be required to dissect the redundant and non-
redundant functions of the individual ATPase subunits,
which may vary in different cells depending upon the
relative abundance of BRM and BRG1.
Broadly speaking, it is clear that the SWI/SNF
complexes are required for a number of processes that
are critical for cell cycle checkpoint control and
differentiation. Abrogation of the normal control
processes is essential for tumor growth and progression,
and loss-of-function mutations in the RB and p53
pathways are among the most common oncogenic
events. Mutations that affect cellular adhesion are
essential for tumor progression and metastases, and
other mutations are required to suppress the process of
anoikis, which is normally triggered by the disruption of
cellular adhesion and polarity. There is evidence that
links all of these events to SWI/SNF activity, and the
preponderance of data suggests that the SWI/SNF
complexes function as tumor suppressors. From a
mechanistic standpoint, it is clear that we have much
to learn about how the SWI/SNF complexes control
these processes. A critical question relates to the
numerous observations that suggest that all SWI/SNF
components are not equivalent in this respect. For
example, loss of BAF47 is rare and is associated with a
relatively small subset of tumor types, whereas loss of
BRM and BRG1 is relatively common and is observed in
a wide variety of solid tumors. Loss of BRM appears to
predispose to tumor formation, whereas loss of BRG1
appears to be lethal in non-transformed cells, but to
promote tumor progression in cells that have acquired
oncogenic mutations. These observations seem to
provide a rational basis for understanding why loss of
both BRG1 and BRM is more common in tumors than
loss of either alone. Furthermore, the connection
between BRG1/BRM and tumor suppressors such as
RB and p53 suggests that the loss of the SWI/SNF
catalytic subunits represents an alternative route to
inactivation of checkpoint control in the absence of
loss-of-function mutations to the RB and p53 pathways.
SWI/SNF and cancer
D Reisman et al
Data from our laboratory and several others suggest that
the etiology of 10–20% of all solid tumors is dependent
upon loss of both BRM and BRG1. Such observations
emphasize the need for additional studies to determine
how these proteins individually and jointly impinge upon
proliferation, survival and progression of tumor cells.
From a translational perspective, one is drawn to the
observations (1) that the re-introduction of BRM into
cells that have lost both BRM and BRG1 appears to
cause terminal differentiation, or at least irreversible
withdrawal from the cell cycle and (2) that BRM is
epigenetically silenced and can, in theory, be induced in
tumor cells. The initial work with HDAC inhibitors
indicates that it may be possible to develop specific
HDAC inhibitors that will induce BRM but will not
result in the accumulation of inactive, acetylated BRM
protein. Such drugs could have wide applicability in the
treatment of tumors that have lost BRM and BRG1,
and the number of such tumors is quite significant. The
link between SWI/SNF activity and DNA repair is also
of potential clinical interest. As loss of BRG1 appears to
increase radiosensitivity of tumor cells, it is plausible
that inhibitors of this ATPase could be used as
adjuvants in radiotherapy. We are only now beginning
to recognize the clinical potential of BRM/BRG1 as
either therapeutic targets or biomarkers of chemo- or
radiotherapy, and the promise of these two gene
products in individualized medicine is significant.
Abrams E, Neigeborn L, Carlson M. (1986). Molecular analysis of SNF2
and SNF5, genes required for expression of glucose-repressible genes in
Saccharomyces cerevisiae. Mol Cell Biol 6: 3643–3651.
Agalioti T, Lomvardas S, Parekh B, Yie J, Maniatis T, Thanos D.
(2000). Ordered recruitment of chromatin modifying and general
transcription factors to the IFN-beta promoter [In Process
Citation]. Cell 103: 667–678.
An HX, Claas A, Savelyeva L, Seitz S, Schlag P, Scherneck S et al.
(1999). Two regions of deletion in 9p23–24 in sporadic breast
cancer. Cancer Res 59: 3941–3943.
Aoyagi S, Trotter KW, Archer TK. (2005). ATP-dependent chromatin
remodeling complexes and their role in nuclear receptor-dependent
transcription in vivo. Vitam Horm 70: 281–307.
Armstrong JA, Bieker JJ, Emerson BM. (1998). A SWI/SNF-
related chromatin remodeling complex, E-RC1, is required for
tissue-specific transcriptional regulation by EKLF in vitro. Cell 95:
Armstrong JA, Papoulas O, Daubresse G, Sperling AS, Lis JT, Scott
MP et al. (2002). The Drosophila BRM complex facilitates global
transcription by RNA polymerase II. EMBO J 19: 5245–5254.
Banine F, Bartlett C, Gunawardena R, Muchardt C, Yaniv M,
Knudsen ES et al. (2005). SWI/SNF chromatin-remodeling factors
induce changes in DNA methylation to promote transcriptional
activation. Cancer Res 65: 3542–3547.
Batsche E, Yaniv M, Muchardt C. (2006). The human SWI/SNF
subunit Brm is a regulator of alternative splicing. Nat Struct Mol
Biol 13: 22–29.
Belandia B, Orford RL, Hurst HC, Parker MG. (2002). Targeting of
SWI/SNF chromatin remodelling complexes to estrogen-responsive
genes. EMBO J 21: 4094–4103.
Biegel JA, Fogelgren B, Zhou JY, James CD, Janss AJ, Allen JC et al.
(2000). Mutations of the INI1 rhabdoid tumor suppressor gene in
medulloblastomas and primitive neuroectodermal tumors of the
central nervous system. Clin Cancer Res 6: 2759–2763.
Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CW, Thiele
CJ et al. (2002). The role of INI1 and the SWI/SNF complex in the
development of rhabdoid tumors: meeting summary from the
workshop on childhood atypical teratoid/rhabdoid tumors. Cancer
Res 62: 323–328.
Biegel JA, Pollack IF. (2004). Molecular analysis of pediatric brain
tumors. Curr Oncol Rep 6: 445–452.
Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS et al.
(2000). BRCA1 is associated with a human SWI/SNF-related
complex: linking chromatin remodeling to breast cancer. Cell 102:
Bortvin A, Winston F. (1996). Evidence that Spt6p controls chromatin
structure by a direct interaction with histones. Science 272:
Bourachot B, Yaniv M, Muchardt C. (1999). The activity of
mammalian brm/SNF2alpha is dependent on a high-mobility-
group protein I/Y-like DNA binding domain. Mol Cell Biol 19:
Bourachot B, Yaniv M, Muchardt C. (2003). Growth inhibition by the
mammalian SWI-SNF subunit Brm is regulated by acetylation.
EMBO J 22: 6505–6515.
Bourdeaut F, Freneaux P, Thuille B, Lellouch-Tubiana A, Nicolas A,
Couturier J et al. (2007). hSNF5/INI1-deficient tumours and
rhabdoid tumours are convergent but not fully overlapping entities.
J Pathol 211: 323–330.
Brockmann D, Lehmkuhler O, Schmucker U, Esche H. (2001). The
histone acetyltransferase activity of PCAF cooperates with the
brahma/SWI2-related protein BRG-1 in the activation of the
enhancer A of the MHC class I promoter. Gene 277: 111–120.
Brumby AM, Zraly CB, Horsfield JA, Secombe J, Saint R, Dingwall
AK et al. (2002). Drosophila cyclin E interacts with components of
the Brahma complex. EMBO J 21: 3377–3389.
Bultman S, Gebuhr T, Yee D, La Mantia C, Nicholson J, Gilliam A
et al. (2000). A Brg1 null mutation in the mouse reveals functional
differences among mammalian SWI/SNF complexes. Mol Cell 6:
Bultman SJ, Herschkowitz JI, Godfrey V, Gebuhr TC, Yaniv M,
Perou CM et al. (2008). Characterization of mammary tumors from
Brg1 heterozygous mice. Oncogene 27: 460–468.
Cairns BR, Erdjument-Bromage H, Tempst P, Winston F, Kornberg
RD. (1998). Two actin-related proteins are shared functional
components of the chromatin-remodeling complexes RSC and
SWI/SNF. Mol Cell 2: 639–651.
Carlson M, Laurent BC. (1994). The SNF/SWI family of global
transcriptional activators. Curr Opin Cell Biol 6: 396–402.
Carlson M, Osmond BC, Botstein D. (1981). Mutants of yeast
defective in sucrose utilization. Genetics 98: 25–40.
Chai B, Huang J, Cairns BR, Laurent BC. (2005). Distinct roles for the
RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA
double-strand break repair. Genes Dev 19: 1656–1661.
Chen J, Archer TK. (2005). Regulating SWI/SNF subunit levels
via protein-protein interactions and proteasomal degradation:
BAF155 and BAF170 limit expression of BAF57. Mol Cell Biol
Chi TH, Wan M, Lee PP, Akashi K, Metzger D, Chambon P et al.
(2003). Sequential roles of Brg, the ATPase subunit of BAF
chromatin remodeling complexes, in thymocyte development.
Immunity 19: 169–182.
Chi TH, Wan M, Zhao K, Taniuchi I, Chen L, Littman DR et al.
(2002). Reciprocal regulation of CD4/CD8 expression by SWI/
SNF-like BAF complexes. Nature 418: 195–199.
Chiba H, Muramatsu M, Nomoto A, Kato H. (1994). Two human
homologues of Saccharomyces cerevisiae SWI2/SNF2 and Droso-
phila brahma are transcriptional coactivators cooperating with the
estrogen receptor and the retinoic acid receptor. Nucleic Acids Res
SWI/SNF and cancer
D Reisman et al
Choi EY, Park JA, Sung YH, Kwon H. (2001a). Generation of the
dominant-negative mutant of hArpNbeta: a component of human
SWI/SNF chromatin remodeling complex. Exp Cell Res 271:
Choi YI, Jeon SH, Jang J, Han S, Kim JK, Chung H et al. (2001b).
Notch1 confers a resistance to glucocorticoid-induced apoptosis on
developing thymocytes by down-regulating SRG3 expression. Proc
Natl Acad Sci USA 98: 10267–10272.
Claudio PP, Howard CM, Fu Y, Cinti C, Califano L, Micheli P et al.
(2000). Mutations in the retinoblastoma-related gene RB2/p130 in
primary nasopharyngeal carcinoma. Cancer Res 60: 8–12.
Coisy-Quivy M, Disson O, Roure V, Muchardt C, Blanchard JM,
Dantonel JC. (2006). Role for brm in cell growth control. Cancer
Res 66: 5069–5076.
Collins RT, Furukawa T, Tanese N, Treisman JE. (1999). Osa
associates with the Brahma chromatin remodeling complex
and promotes the activation of some target genes. EMBO J 18:
Cote J, Quinn J, Workman JL, Peterson CL. (1994). Stimulation of
GAL4 derivative binding to nucleosomal DNA by the yeast SWI/
SNF complex. Science 265: 53–60.
Cui K, Tailor P, Liu H, Chen X, Ozato K, Zhao K. (2004). The
chromatin-remodeling BAF complex mediates cellular antiviral
activities by promoter priming. Mol Cell Biol 24: 4476–4486.
Dahiya A, Gavin MR, Luo RX, Dean DC. (2000). Role of
the LXCXE binding site in Rb function. Mol Cell Biol 20:
Dai Y, Ngo D, Jacob J, Forman LW, Faller DV. (2008). Prohibitin
and the SWI/SNF ATPase subunit BRG1 are required for effective
androgen antagonist-mediated transcriptional repression of andro-
gen receptor-regulated genes. Carcinogenesis 29: 1725–1733.
de La Serna IL, Carlson KA, Imbalzano AN. (2001a). Mammalian
SWI/SNF complexes promote MyoD-mediated muscle differentia-
tion. Nat Genet 27: 187–190.
de La Serna IL, Roy K, Carlson KA, Imbalzano AN. (2001b). MyoD
can induce cell cycle arrest but not muscle differentiation in the
presence of dominant negative SWI/SNF chromatin remodeling
enzymes. J Biol Chem 276: 41486–41491.
Debril MB, Gelman L, Fayard E, Annicotte JS, Rocchi S, Auwerx J.
(2004). Transcription factors and nuclear receptors interact with the
SWI/SNF complex through the BAF60c subunit. J Biol Chem 279:
DeCristofaro MF, Betz BL, Rorie CJ, Reisman DN, Wang W,
Weissman BE. (2001). Characterization of SWI/SNF protein
expression in human breast cancer cell lines and other malignancies.
J Cell Physiol 186: 136–145.
Dingwall AK, Beek SJ, McCallum CM, Tamkun JW, Kalpana GV,
Goff SP et al. (1995). The Drosophila snr1 and brm proteins are
related to yeast SWI/SNF proteins and are components of a large
protein complex. Mol Biol Cell 6: 777–791.
Doan DN, Veal TM, Yan Z, Wang W, Jones SN, Imbalzano AN.
(2004). Loss of the INI1 tumor suppressor does not impair the
expression of multiple BRG1-dependent genes or the assembly of
SWI/SNF enzymes. Oncogene 23: 3462–3473.
Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J et al.
(1994). The retinoblastoma protein and BRG1 form a complex and
cooperate to induce cell cycle arrest. Cell 79: 119–130.
Eiriksdottir G, Sigurdsson A, Jonasson JG, Agnarsson BA, Sigurdsson
H, Gudmundsson J et al. (1995). Loss of heterozygosity on
chromosome 9 in human breast cancer: association with clinical
variables and genetic changes at other chromosome regions. Int J
Cancer 64: 378–382.
Elfring LK, Deuring R, McCallum CM, Peterson CL, Tamkun JW.
(1994). Identification and characterization of Drosophila relatives of
the yeast transcriptional activator SNF2/SWI2. Mol Cell Biol 14:
Flajollet S, Lefebvre B, Cudejko C, Staels B, Lefebvre P. (2007). The
core component of the mammalian SWI/SNF complex SMARCD3/
BAF60c is a coactivator for the nuclear retinoic acid receptor. Mol
Cell Endocrinol 270: 23–32.
Foster KS, McCrary WJ, Ross JS, Wright CF. (2006). Members of the
hSWI/SNF chromatin remodeling complex associate with and are
phosphorylated by protein kinase B/Akt. Oncogene 25: 4605–4612.
Fry CJ, Peterson CL. (2001). Chromatin remodeling enzymes: who’s
on first? Curr Biol 11: R185–R197.
Fryer CJ, Archer TK. (1998). Chromatin remodelling by the
glucocorticoid receptor requires the BRG1 complex. Nature 393:
Fukuoka J, Fujii T, Shih JH, Dracheva T, Meerzaman D, Player A
et al. (2004). Chromatin remodeling factors and BRM/BRG1
expression as prognostic indicators in non-small cell lung cancer.
Clin Cancer Res 10: 4314–4324.
Gaillard H, Fitzgerald DJ, Smith CL, Peterson CL, Richmond TJ,
Thoma F. (2003).Chromatin remodeling
UV-damaged nucleosomes and modulate DNA damage accessibility
to photolyase. J Biol Chem 278: 17655–17663.
Gao CF, Ren S, Wang J, Zhang SL, Jin F, Nakajima T et al. (2002).
P130 and its truncated form mediate p53-induced cell cycle arrest in
Rb(?/?) Saos2 cells. Oncogene 21: 7569–7579.
Gao X, Tate P, Hu P, Tjian R, Skarnes WC, Wang Z. (2008). ES cell
pluripotency and germ-layer formation require the SWI/SNF
chromatin remodeling component BAF250a. Proc Natl Acad Sci
USA 105: 6656–6661.
Gebuhr TC, Kovalev GI, Bultman S, Godfrey V, Su L, Magnuson T.
(2003). The role of Brg1, a catalytic subunit of mammalian
chromatin-remodeling complexes, in T cell development. J Exp
Med 198: 1937–1949.
Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD.
new regions of allelic loss, differences between small cell lung
cancer and non-small cell lung cancer, and loci clustering. Cancer
Res 60: 4894–4906.
Glaros S, Cirrincione GM, Muchardt C, Kleer CG, Michael CW,
Reisman D. (2007). The reversible epigenetic silencing of BRM:
implications for clinical targeted therapy. Oncogene 26: 7058–7066.
Glaros S, Cirrincione GM, Palanca A, Metzger D, Reisman D. (2008).
Targeted knockout of BRG1 potentiates lung cancer development.
Cancer Res 68: 3689–3696.
Golding A, Chandler S, Ballestar E, Wolffe AP, Schlissel MS. (1999).
Nucleosome structure completely inhibits in vitro cleavage by the
V(D)J recombinase. EMBO J 18: 3712–3723.
Gong F, Fahy D, Liu H, Wang W, Smerdon MJ. (2008). Role of the
mammalian SWI/SNF chromatin remodeling complex in the
cellular response to UV damage. Cell Cycle 7: 1067–1074.
Gorlov I. (2005). Identification of a novel lung cancer candidate
susceptibility gene using a familial aggregation approach. Proceed-
ings of the 97th Annual AACR Meeting, Washington, DC 3: 41.
Grand F, Kulkarni S, Chase A, Goldman JM, Gordon M, Cross NC.
(1999). Frequent deletion of hSNF5/INI1, a component of the
SWI/SNF complex, in chronic myeloid leukemia. Cancer Res 59:
Gunduz E, Gunduz M, Ouchida M, Nagatsuka H, Beder L, Tsujigiwa
H et al. (2005). Genetic and epigenetic alterations of BRG1 promote
oral cancer development. Int J Oncol 26: 201–210.
Han D, Jeon S, Sohn DH, Lee C, Ahn S, Kim WK et al. (2008).
SRG3, a core component of mouse SWI/SNF complex, is
essential for extra-embryonic vascular development. Dev Biol 315:
Hara R, Sancar A. (2002). The SWI/SNF chromatin-remodeling factor
stimulates repair by human excision nuclease in the mononucleo-
some core particle. Mol Cell Biol 22: 6779–6787.
Hassan AH, Neely KE, Vignali M, Reese JC, Workman JL. (2001).
Promoter targeting of chromatin-modifying complexes. Front Biosci
Hendricks KB, Shanahan F, Lees E. (2004). Role for BRG1 in cell
cycle control and tumor suppression. Mol Cell Biol 24: 362–376.
Hill DA, Chiosea S, Jamaluddin S, Roy K, Fischer AH, Boyd DD
et al. (2004). Inducible changes in cell size and attachment area due
to expression of a mutant SWI/SNF chromatin remodeling enzyme.
J Cell Sci 117: 5847–5854.
SWI/SNF and cancer
D Reisman et al
Hirschhorn JN, Brown SA, Clark CD, Winston F. (1992). Evidence
that SNF2/SWI2 and SNF5 activate transcription in yeast by
altering chromatin structure. Genes Dev 6: 2288–2298.
Hong CY, Suh JH, Kim K, Gong EY, Jeon SH, Ko M et al. (2005).
Modulation of androgen receptor transactivation by the SWI3-
related gene product (SRG3) in multiple ways. Mol Cell Biol 25:
Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK. (2003).
BAF60a mediates critical interactions between nuclear receptors
and the BRG1 chromatin-remodeling complex for transactivation.
Mol Cell Biol 23: 6210–6220.
Huang J, Zhao YL, Li Y, Fletcher JA, Xiao S. (2007). Genomic and
functional evidence for an ARID1A tumor suppressor role. Genes
Chromosomes Cancer 46: 745–750.
Huang M, Qian F, Hu Y, Ang C, Li Z, Wen Z. (2002). Chromatin-
remodelling factor BRG1 selectively activates a subset of interferon-
alpha-inducible genes. Nat Cell Biol 4: 774–781.
Hurlstone AF, Olave IA, Barker N, van Noort M, Clevers H. (2002).
Cloning and characterization of hELD/OSA1, a novel BRG1
interacting protein. Biochem J 364: 255–264.
Ichinose H, Garnier JM, Chambon P, Losson R. (1997). Ligand-
dependent interaction between the estrogen receptor and the human
homologues of SWI2/SNF2. Gene 188: 95–100.
Imbalzano AN, Kwon H, Green MR, Kingston RE. (1994).
Facilitated binding of TATA-binding protein to nucleosomal
DNA. Nature 370: 481–485.
Indra AK, Dupe V, Bornert JM, Messaddeq N, Yaniv M, Mark M
et al. (2005). Temporally controlled targeted somatic mutagenesis in
embryonic surface ectoderm and fetal epidermal keratinocytes
unveils two distinct developmental functions of BRG1 in limb
morphogenesis and skin barrier formation. Development 132:
Inoue H, Furukawa T, Giannakopoulos S, Zhou S, King DS, Tanese
N. (2002). Largest subunits of the human SWI/SNF chromatin
remodeling complex promote transcriptional activation by steroid
hormone receptors. J Biol Chem 27: 27.
Ito T, Yamauchi M, Nishina M, Yamamichi N, Mizutani T, Ui M
et al. (2001). Identification of SWI/SNF complex subunit BAF60a
as a determinant of transactivation potential of Fos/Jun dimers.
J Biol Chem 276: 2852–2857.
Jin YT, Myers J, Tsai ST, Goepfert H, Batsakis JG, el-Naggar AK.
(1999). Genetic alterations in oral squamous cell carcinoma of
young adults. Oral Oncol 35: 251–256.
Kal AJ, Mahmoudi T, Zak NB, Verrijzer CP. (2000). The Drosophila
brahma complex is an essential coactivator for the trithorax group
protein zeste. Genes Dev 14: 1058–1071.
Kalpana GV, Marmon S, Wang W, Crabtree GR, Goff SP. (1994).
Binding and stimulation of HIV-1 integrase by a human homolog
of yeast transcription factor SNF5 [see comments]. Science 266:
Kang H, Cui K, Zhao K. (2004). BRG1 controls the activity of the
retinoblastoma protein via regulation of p21CIP1/WAF1/SDI. Mol
Cell Biol 24: 1188–1199.
Kapic A, Helmbold H, Reimer R, Klotzsche O, Deppert W, Bohn W.
(2006). Cooperation between p53 and p130(Rb2) in induction of
cellular senescence. Cell Death Differ 13: 324–334.
Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR.
(1993). BRG1 contains a conserved domain of the SWI2/SNF2
family necessary for normal mitotic growth and transcription.
Nature 366: 170–174.
Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui
D et al. (2003). The chromatin-remodeling complex WINAC targets
a nuclear receptor to promoters and is impaired in Williams
syndrome. Cell 113: 905–917.
Klochendler-Yeivin A, Picarsky E, Yaniv M. (2006). Increased DNA
damage sensitivity and apoptosis in cells lacking the Snf5/Ini1
subunit of the SWI/SNF chromatin remodeling complex. Mol Cell
Biol 26: 2661–2674.
Ko M, Jang J, Ahn J, Lee K, Chung H, Jeon SH et al. (2004). T cell
receptor signaling inhibits glucocorticoid-induced apoptosis by
repressing the SRG3 expression via Ras activation. J Biol Chem
Kozmik Z, Machon O, Kralova J, Kreslova J, Paces J, Vlcek C. (2001).
Characterization of mammalian orthologues of the Drosophila osa
gene: cDNA cloning, expression, chromosomal localization, and
direct physical interaction with Brahma chromatin-remodeling
complex. Genomics 73: 140–148.
Kruger W, Peterson CL, Sil A, Coburn C, Arents G, Moudrianakis
EN et al. (1995). Amino acid substitutions in the structured
domains of histones H3 and H4 partially relieve the requirement
of the yeast SWI/SNF complex for transcription. Genes Dev 9:
Kwon H, Imbalzano AN, Khavari PA, Kingston RE, Green MR.
(1994). Nucleosome disruption and enhancement of activator
binding by a human SW1/SNF complex [see comments]. Nature
Kwon J, Morshead KB, Guyon JR, Kingston RE, Oettinger MA.
(2000). Histone acetylation and hSWI/SNF remodeling act in
concert to stimulate V(D)J cleavage of nucleosomal DNA. Mol Cell
Lee CH, Murphy MR, Lee JS, Chung JH. (1999). Targeting a SWI/
globin promoter in erythroid cells. Proc Natl Acad Sci USA 96:
Lee D, Kim JW, Seo T, Hwang SG, Choi EJ, Choe J. (2002). SWI/
SNF complex interacts with tumor suppressor p53 and is necessary
for the activation of p53-mediated transcription. J Biol Chem 277:
Lee JH, Chang SH, Shim JH, Lee JY, Yoshida M, Kwon H. (2003).
Cytoplasmic localization and
of BAF53, a component of chromatin-modifying complexes.
Mol Cells 16: 78–83.
Lee JH, Lee JY, Chang SH, Kang MJ, Kwon H. (2005). Effects of Ser2
and Tyr6 mutants of BAF53 on cell growth and p53-dependent
transcription. Mol Cells 19: 289–293.
Lee K, Kang MJ, Kwon SJ, Kwon YK, Kim KW, Lim JH et al.
(2007a). Expansion of chromosome territories with chromatin
decompaction in BAF53-depleted interphase cells. Mol Biol Cell
Lee K, Shim JH, Kang MJ, Kim JH, Ahn JS, Yoo SJ et al. (2007b).
Association of BAF53 with mitotic chromosomes. Mol Cells 24:
LeGouy E, Thompson EM, Muchardt C, Renard JP. (1998).
Differential preimplantation regulation of two mouse homologues
of the yeast SWI2 protein. Dev Dyn 212: 38–48.
Lemon B, Inouye C, King DS, Tjian R. (2001). Selectivity of
chromatin-remodelling cofactors for ligand-activated transcription.
Nature 414: 924–928.
Lickert H, Takeuchi JK, Von Both I, Walls JR, McAuliffe F,
Adamson SL et al. (2004). Baf60c is essential for function of BAF
chromatin remodelling complexes in heart development. Nature 432:
Link KA, Burd CJ, Williams E, Marshall T, Rosson G, Henry E
et al. (2005). BAF57 governs androgen receptor action and
androgen-dependent proliferation through SWI/SNF. Mol Cell Biol
Liu H, Kang H, Liu R, Chen X, Zhao K. (2002). Maximal induction
of a subset of interferon target genes requires the chromatin-
remodeling activity of the BAF complex. Mol Cell Biol 22:
Liu K, Luo Y, Lin FT, Lin WC. (2004). TopBP1 recruits
pRb-independent and E2F1-specific control for cell survival. Genes
Dev 18: 673–686.
Liu R, Liu H, Chen X, Kirby M, Brown PO, Zhao K. (2001).
Regulation of CSF1 promoter by the SWI/SNF-like BAF complex.
Cell 106: 309–318.
Manda R, Kohno T, Hamada K, Takenoshita S, Kuwano H,
Yokota J. (2000). Absence of hSNF5/INI1 mutation in human
lung cancer. Cancer Lett 153: 57–61.
SWI/SNF and cancer
D Reisman et al
Marshall TW, Link KA, Petre-Draviam CE, Knudsen KE. (2003).
Differential requirement of SWI/SNF for androgen receptor
activity. J Biol Chem 278: 30605–30613.
Martens JA, Winston F. (2003). Recent advances in understanding
chromatin remodeling by Swi/Snf complexes. Curr Opin Genet Dev
Medina PP, Carretero J, Fraga MF, Esteller M, Sidransky D, Sanchez-
Cespedes M. (2004). Genetic and epigenetic screening for gene
alterations of the chromatin-remodeling factor, SMARCA4/BRG1,
in lung tumors. Genes Chromosomes Cancer 41: 170–177.
Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J
et al. (2008). Frequent BRG1/SMARCA4-inactivating mutations in
human lung cancer cell lines. Hum Mutat 29: 617–622.
Menoni H, Gasparutto D, Hamiche A, Cadet J, Dimitrov S, Bouvet P
et al. (2007). ATP-dependent chromatin remodeling is required for
base excision repair in conventional but not in variant H2A.Bbd
nucleosomes. Mol Cell Biol 27: 5949–5956.
Mizutani T, Ito T, Nishina M, Yamamichi N, Watanabe A, Iba H.
(2002). Maintenance of integrated proviral gene expression requires
Brm, a catalytic subunit of SWI/SNF complex. J Biol Chem 277:
Monahan BJ, Villen J, Marguerat S, Bahler J, Gygi SP, Winston F.
(2008). Fission yeast SWI/SNF and RSC complexes show composi-
tional and functional differences from budding yeast. Nat Struct
Mol Biol 15: 873–880.
Morrison AJ, Shen X. (2006). Chromatin modifications in DNA
repair. Results Probl Cell Differ 41: 109–125.
Morshead KB, Ciccone DN, Taverna SD, Allis CD, Oettinger MA.
(2003). Antigen receptor loci poised for V(D)J rearrangement
are broadly associated with BRG1 and flanked by peaks of
histone H3 dimethylated at lysine 4. Proc Natl Acad Sci USA 100:
Muchardt C, Bourachot B, Reyes JC, Yaniv M. (1998). ras
transformation is associated with decreased expression of the brm/
SNF2alpha ATPase from the mammalian SWI–SNF complex.
EMBO J 17: 223–231.
Muchardt C, Yaniv M. (1993). A human homologue of Saccharomyces
cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates
transcriptional activation by the glucocorticoid receptor. EMBO J
Muchardt C, Yaniv M. (1999a). ATP-dependent chromatin remodel-
ling: SWI/SNF and Co. are on the job. J Mol Biol 293: 187–198.
Muchardt C, Yaniv M. (1999b). The mammalian SWI/SNF complex
and the control of cell growth. Semin Cell Dev Biol 10: 189–195.
Muchardt C, Yaniv M. (2001). When the SWI/SNF complex
remodels.the cell cycle. Oncogene 20: 3067–3075.
Mudhasani R, Fontes JD. (2002). The class II transactivator requires
brahma-related gene 1 to activate transcription of major histocom-
patibility complex class II genes. Mol Cell Biol 22: 5019–5026.
Murphy DJ, Hardy S, Engel DA. (1999). Human SWI–SNF
component BRG1 represses transcription of the c-fos gene. Mol
Cell Biol 19: 2724–2733.
Nagl Jr NG, Wang X, Patsialou A, Van Scoy M, Moran E. (2007).
Distinct mammalian SWI/SNF chromatin remodeling complexes
with opposing roles in cell-cycle control. EMBO J 26: 752–763.
Nagl Jr NG, Zweitzig DR, Thimmapaya B, Beck Jr GR, Moran E.
(2006). The c-myc gene is a direct target of mammalian SWI/SNF-
related complexes during differentiation-associated cell cycle arrest.
Cancer Res 66: 1289–1293.
Nasmyth K, Shore D. (1987). Transcriptional regulation in the yeast
life cycle. Science 237: 1162–1170.
Neely KE, Workman JL. (2002). The complexity of chromatin
remodeling and its links to cancer. Biochim Biophys Acta 1603:
Neigeborn L, Carlson M. (1984). Genes affecting the regulation of
SUC2 gene expression by glucose repression in Saccharomyces
cerevisiae. Genetics 108: 845–858.
Neigeborn L, Carlson M. (1987). Mutations causing constitutive
invertase synthesis in yeast: genetic interactions with snf mutations.
Genetics 115: 247–253.
Neville EM, Stewart M, Myskow M, Donnelly RJ, Field JK. (1995).
Loss of heterozygosity at 9p23 defines a novel locus in non-small cell
lung cancer. Oncogene 11: 581–585.
Nie Z, Xue Y, Yang D, Zhou S, Deroo BJ, Archer TK et al. (2000).
A specificity and targeting subunit of a human SWI/SNF
family-related chromatin-remodeling complex. Mol Cell Biol 20:
Nie Z, Yan Z, Chen EH, Sechi S, Ling C, Zhou S et al. (2003). Novel
SWI/SNF chromatin-remodeling complexes contain a mixed-line-
age leukemia chromosomal translocation partner. Mol Cell Biol 23:
Osipovich O, Cobb RM, Oestreich KJ, Pierce S, Ferrier P, Oltz EM.
(2007). Essential function for SWI-SNF chromatin-remodeling
complexes in the promoter-directed assembly of Tcrb genes. Nat
Immunol 8: 809–816.
Osley MA, Tsukuda T, Nickoloff JA. (2007). ATP-dependent
chromatin remodeling factors and DNA damage repair. Mutat
Res 618: 65–80.
Ostlund Farrants AK, Blomquist P, Kwon H, Wrange O. (1997).
Glucocorticoid receptor-glucocorticoid response element binding
stimulates nucleosome disruption by the SWI/SNF complex. Mol
Cell Biol 17: 895–905.
Otsuki T, Furukawa Y, Ikeda K, Endo H, Yamashita T, Shinohara A
et al. (2001). Fanconi anemia protein, FANCA, associates with
BRG1, a component of the human SWI/SNF complex. Hum Mol
Genet 10: 2651–2660.
Papoulas O, Beek SJ, Moseley SL, McCallum CM, Sarte M, Shearn A
et al. (1998). The Drosophila trithorax group proteins BRM, ASH1
and ASH2 are subunits of distinct protein complexes. Development
Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN et al.
(2006). Mammalian SWI/SNF complexes facilitate DNA double-
strand break repair by promoting gamma-H2AX induction.
EMBO J 25: 3986–3997.
Patenge N, Elkin SK, Oettinger MA. (2004). ATP-dependent
remodeling by SWI/SNF and ISWI proteins stimulates V(D)J
cleavage of 5 S arrays. J Biol Chem 279: 35360–35367.
Peterson CL. (1998). SWI/SNF complex: dissection of a chromatin
remodeling cycle. Cold Spring Harb Symp Quant Biol 63: 545–552.
Peterson CL, Dingwall A, Scott MP. (1994). Five SWI/SNF gene
products are components of a large multisubunit complex required
for transcriptional enhancement [see comments]. Proc Natl Acad Sci
USA 91: 2905–2908.
PetersonCL, Tamkun JW.(1995).
a chromatin remodeling machine? Trends Biochem Sci 20: 143–146.
Peterson CL, Workman JL. (2000). Promoter targeting and chromatin
remodeling by the SWI/SNF complex. Curr Opin Genet Dev 10:
Peterson CL, Zhao Y, Chait BT. (1998). Subunits of the yeast SWI/
SNF complex are members of the actin-related protein (ARP)
family. J Biol Chem 273: 23641–23644.
Phelan ML, Sif S, Narlikar GJ, Kingston RE. (1999). Reconstitution
of a core chromatin remodeling complex from SWI/SNF subunits.
Mol Cell 3: 247–253.
Pottier N, Cheok MH, Yang W, Assem M, Tracey L, Obenauer JC
et al. (2007). Expression of SMARCB1 modulates steroid sensitivity
in human lymphoblastoid cells: identification of a promoter SNP
that alters PARP1 binding and SMARCB1 expression. Hum Mol
Genet 16: 2261–2271.
Reisman DN, Sciarrotta J, Bouldin TW, Weissman BE, Funkhouser
WK. (2005). The expression of the SWI/SNF ATPase subunits
BRG1 and BRM in normal human tissues. Appl Immunohistochem
Mol Morphol 13: 66–74.
Reisman DN, Sciarrotta J, Wang W, Funkhouser WK, Weissman BE.
(2003). Loss of BRG1/BRM in human lung cancer cell lines and
primary lung cancers: correlation with poor prognosis. Cancer Res
Reisman DN, Strobeck MW, Betz BL, Sciariotta J, Funkhouser Jr W,
Murchardt C et al. (2002). Concomitant down-regulation of BRM
and BRG1 in human tumor cell lines: differential effects on
SWI/SNF and cancer
D Reisman et al
RB-mediated growth arrest vs CD44 expression. Oncogene 21: Download full-text
Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M.
(1998). Altered control of cellular proliferation in the absence of
mammalian brahma (SNF2alpha). EMBO J 17: 6979–6991.
Ring HZ, Vameghi-Meyers V, Wang W, Crabtree GR, Francke U.
(1998). Five SWI/SNF-related, matrix-associated, actin-dependent
regulator of chromatin (SMARC) genes are dispersed in the human
genome. Genomics 51: 140–143.
Roberts CW, Leroux MM, Fleming MD, Orkin SH. (2002).
inversion of the tumor suppressor gene Snf5. Cancer Cell 2:
Roberts CW, Orkin SH. (2004). The SWI/SNF complex—chromatin
and cancer. Nat Rev Cancer 4: 133–142.
Rousseau-Merck MF, Versteege I, Legrand I, Couturier J, Mairal A,
Delattre O et al. (1999). hSNF5/INI1 inactivation is mainly
associated with homozygous deletions and mitotic recombinations
in rhabdoid tumors. Cancer Res 59: 3152–3156.
Roy K, De La Serna IL, Imbalzano AN. (2002). The myogenic basic
helix-loop-helix family of transcription factors show similar
requirements for SWI/SNF chromatin remodeling enzymes during
muscle differentiation in culture. J Biol Chem 8: 8.
Sabah M, Cummins R, Leader M, Kay E. (2005). Leiomyosarcoma
and malignant fibrous histiocytoma share similar allelic imbalance
pattern at 9p. Virchows Arch 446: 251–258.
Saha A, Wittmeyer J, Cairns BR. (2006). Mechanisms for nucleosome
movement by ATP-dependent chromatin remodeling complexes.
Results Probl Cell Differ 41: 127–148.
Sarkar S, Roy BC, Hatano N, Aoyagi T, Gohji K, Kiyama R. (2002).
A novel ankyrin repeat-containing gene (Kank) located at 9p24
is a growth suppressor of renal cell carcinoma. J Biol Chem 277:
Schnitzler G, Sif S, Kingston RE. (1998). Human SWI/SNF
interconverts a nucleosome between its base state and a stable
remodeled state. Cell 94: 17–27.
Schwartz YB, Boykova T, Belyaeva ES, Ashburner M, Zhimulev IF.
(2004). Molecular characterization of the singed wings locus of
Drosophila melanogaster. BMC Genet 5: 15.
Sekine I, Sato M, Sunaga N, Toyooka S, Peyton M, Parsons R et al.
(2005). The 3p21 candidate tumor suppressor gene BAF180
is normally expressed in human lung cancer. Oncogene 24:
Sentani K, Oue N, Kondo H, Kuraoka K, Motoshita J, Ito R et al.
(2001). Increased expression but not genetic alteration of BRG1, a
component of the SWI/SNF complex, is associated with the
advanced stage of human gastric carcinomas. Pathobiology 69:
Seo S, Herr A, Lim JW, Richardson GA, Richardson H, Kroll KL.
(2005a). Geminin regulates neuronal differentiation by antagonizing
Brg1 activity. Genes Dev 19: 1723–1734.
Seo S, Richardson GA, Kroll KL. (2005b). The SWI/SNF chromatin
remodeling protein Brg1 is required for vertebrate neurogenesis and
mediates transactivation of Ngn and NeuroD. Development 132:
Sevenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler
M, Birnbaum D et al. (1999a). Spectrum of hSNF5/INI1 somatic
mutations in human cancer and genotype- phenotype correlations.
Hum Mol Genet 8: 2359–2368.
Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R,
Delattre O. (1999b). Constitutional mutations of the hSNF5/INI1
gene predispose to a variety of cancers. Am J Hum Genet 65:
Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E. (1999). Cyclin
E associates with BAF155 and BRG1, components of the
mammalian SWI–SNF complex, and alters the ability of BRG1 to
induce growth arrest. Mol Cell Biol 19: 1460–1469.
Shundrovsky A, Smith CL, Lis JT, Peterson CL, Wang MD. (2006).
Probing SWI/SNF remodeling of the nucleosome by unzipping
single DNA molecules. Nat Struct Mol Biol 13: 549–554.
Smith CL, Horowitz-Scherer R, Flanagan JF, Woodcock CL, Peterson
CL. (2003). Structural analysis of the yeast SWI/SNF chromatin
remodeling complex. Nat Struct Biol 10: 141–145.
Smith CL, Peterson CL. (2005). A conserved Swi2/Snf2 ATPase motif
couples ATP hydrolysis to chromatin remodeling. Mol Cell Biol 25:
Sohn DH, Lee KY, Lee C, Oh J, Chung H, Jeon SH et al. (2007).
SRG3 interacts directly with the major components of the SWI/
SNF chromatin remodeling complex and protects them from
proteasomal degradation. J Biol Chem 282: 10614–10624.
Spicuglia S, Kumar S, Yeh JH, Vachez E, Chasson L, Gorbatch S et al.
(2002). Promoter activation by enhancer-dependent and -indepen-
dent loading of activator and coactivator complexes. Mol Cell 10:
Stern M, Jensen R, Herskowitz I. (1984). Five SWI genes are required
for expression of the HO gene in yeast. J Mol Biol 178: 853–868.
Sherman LS, Knudsen ES. (2001). The BRG-1 subunit of the
SWI/SNF complex regulates CD44 expression. J Biol Chem 276:
Strobeck MW, Knudsen KE, Fribourg AF, DeCristofaro MF,
Weissman BE, Imbalzano AN et al. (2000). BRG-1 is required
for RB-mediated cell cycle arrest. Proc Natl Acad Sci USA 97:
Strobeck MW, Reisman DN, Gunawardena RW, Betz BL, Angus SP,
Knudsen KE et al. (2002). Compensation of BRG-1 function by
Brm: insight into the role of the core SWI/SNF subunits in RB-
signaling. J Biol Chem 21: 21.
Strober BE, Dunaief JL, Guha, Goff SP. (1996). Functional
interactions between the hBRM/hBRG1 transcriptional activators
and the pRB family of proteins. Mol Cell Biol 16: 1576–1583.
Sudarsanam P, Iyer VR, Brown PO, Winston F. (2000). Whole-
genome expression analysis of snf/swi mutants of Saccharomyces
cerevisiae. Proc Natl Acad Sci USA 97: 3364–3369.
Sumi-Ichinose C, Ichinose H, Metzger D, Chambon P. (1997).
SNF2beta-BRG1 is essential for the viability of F9 murine
embryonal carcinoma cells. Mol Cell Biol 17: 5976–5986.
Takeuchi JK, Lickert H, Bisgrove BW, Sun X, Yamamoto M,
Chawengsaksophak K et al. (2007). Baf60c is a nuclear Notch
signaling component required for the establishment of left-right
asymmetry. Proc Natl Acad Sci USA 104: 846–851.
Tamkun JW. (1995). The role of brahma and related proteins in
transcription and development. Curr Opin Genet Dev 5: 473–477.
Tamkun JW, Deuring R, Scott MP, Kissinger M, Pattatucci AM,
Kaufman TC et al. (1992). brahma: a regulator of Drosophila
homeotic genes structurally related to the yeast transcriptional
activator SNF2/SWI2. Cell 68: 561–572.
Tripathi A, Dasgupta S, Roy A, Sengupta A, Roy B, Roychowdhury S
et al. (2003). Sequential deletions in both arms of chromosome 9
are associated with the development of head and neck squamous
cell carcinoma in Indian patients. J Exp Clin Cancer Res 22:
Trotter KW, Archer TK. (2004). Reconstitution of glucocorticoid
receptor-dependent transcription in vivo. Mol Cell Biol 24:
Trotter KW, Archer TK. (2008). The BRG1 transcriptional coregu-
lator. Nucl Recept Signal 6: e004.
Trouche D, Le Chalony C, Muchardt C, Yaniv M, Kouzarides T.
(1997). RB and hbrm cooperate to repress the activation functions
of E2F1. Proc Natl Acad Sci USA 94: 11268–11273.
Underhill C, Qutob MS, Yee SP, Torchia J. (2000). A novel nuclear
receptor corepressor complex, N-CoR, contains components of the
mammalian SWI/SNF complex and the corepressor KAP-1. J Biol
Chem 275: 40463–40470.
Valdman A, Nordenskjold A, Fang X, Naito A, Al-Shukri S, Larsson
C et al. (2003). Mutation analysis of the BRG1 gene in prostate
cancer clinical samples. Int J Oncol 22: 1003–1007.
Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P,
Handgretinger R et al. (1998). Truncating mutations of hSNF5/
INI1 in aggressive paediatric cancer. Nature 394: 203–206.
SWI/SNF and cancer
D Reisman et al