Epigenetic Dysregulation in Cancer

Article (PDF Available)inAmerican Journal Of Pathology 175(4):1353-61 · September 2009with42 Reads
DOI: 10.2353/ajpath.2009.081142 · Source: PubMed
One of the great paradoxes in cellular differentiation is how cells with identical DNA sequences differentiate into so many different cell types. The mechanisms underlying this process involve epigenetic regulation mediated by alterations in DNA methylation, histone posttranslational modifications, and nucleosome remodeling. It is becoming increasingly clear that disruption of the "epigenome" as a result of alterations in epigenetic regulators is a fundamental mechanism in cancer. This has major implications for the future of both molecular diagnostics as well as cancer chemotherapy.
Biological Perspectives
Epigenetic Dysregulation in Cancer
Andrew G. Muntean and Jay L. Hess
From the Department of Pathology, University of Michigan
Medical School, Ann Arbor, Michigan
One of the great paradoxes in cellular differentiation
is how cells with identical DNA sequences differenti-
ate into so many different cell types. The mechanisms
underlying this process involve epigenetic regulation
mediated by alterations in DNA methylation, histone
posttranslational modifications , and nucleosome re-
modeling. It is becoming increasingly clear that dis-
ruption of the “epigenome” as a result of alterations
in epigenetic regulators is a fundamental mechanism
in cancer. This has major implications for the fu-
ture of both molecular diagnostics as well as cancer
(Am J Pathol 2009, 175:1353–1361; DOI:
Epigenetics is a rapidly evolving field focused on explain-
ing how heritable changes in gene expression occur that
do not involve changes in nucleotide sequence.
netic regulation of transcription can be mediated through
DNA methylation, histone modifications including histone
acetylation, phosphorylation, methylation, ubiquitination,
and proteolysis, and alterations in chromatin remodeling.
Importantly, increasing evidence shows that epigenetic
deregulation is a common mechanism in cancer. The role
of DNA methylation in cancer has been extensively stud-
ied, and a number of excellent reviews have been pub-
lished on this topic.
2– 4
More recently, it has become clear
that histone modifications, as well as disruption of chro-
matin remodeling machinery, play a fundamental role in
cancer, and this is our primary focus in this review. It is
important to recognize that these three types of epige-
netic regulation are highly interdependent. For example,
patterns of histone methylation are important for estab-
lishing patterns of DNA methylation. Chromatin remodel-
ing, in turn, is programmed in part by changes in DNA
methylation and histone modifications.
DNA Methylation
CpG-rich sequences are generally rare in the mammalian
genome except for in so-called CpG islands, which are
associated with centromeres, microsatellite sequences,
and the proximal promoter regions of approximately half
of all genes. CpG-containing sequences are cytosine
methylated by a family of DNA methyltransferases or
DNMTs (to date, unequivocal evidence for DNA dem-
ethylases is lacking). These methyltransferases generally
exempt promoter-associated CpG islands, where 20%
are CpG methylated.
It was recognized over 25 years ago in studies of colon
cancer that patterns of DNA methylation in tumor cells
differed considerably from normal cells.
These early
studies, which detected DNA methylation using methyl-
ation-sensitive restriction enzymes and Southern blotting,
revealed global hypomethylation of DNA sequences
compared with normal cellular counterparts (Figure 1).
Subsequently, many high-throughput techniques have
been developed for CpG methylation profiling, including
restriction landmark genomic screening, bisulfite se-
quencing, differential methylation hybridization, DNA im-
munoprecipitation using antibodies directed against
5-methylcytosine, and array or sequence-based detec-
tion methods, which have confirmed this finding of global
hypomethylation in a variety of cancers.
This hypom-
ethylation, whose mechanism remains poorly under-
stood, may play several roles in oncogenesis, including
increasing genomic instability as well as contributing to
the over expression of genes, such as MAGE, CAGE,
CYCLIND2, S100A4, CD30, as well as loss of imprinting of
genes such as IGF2.
In one well-studied example, loss
of imprinting of the maternally inherited IGF2 allele has
been implicated in the pathogenesis of colorectal cancer
and Wilm’s tumor.
Changes in DNA methylation have
also been associated with chemotherapy resistance. For
example, methylation of the MLH1 gene is associated
with increased resistance to cis-platinum and alkylating
Paradoxically, local hypermethylation of specific
genes also appears to play an important role in cancer
(Figure 1). The first hypermethylated gene identified was
calcitonin, which is hypermethylated in a subset of small
cell carcinoma cases.
This was followed by identifica-
Accepted for publication June 22, 2009.
Address reprint requests to Jay L. Hess, Department of Pathology,
University of Michigan Medical School, 5240 Medical Sciences 1, 1301
Catherine Road, Ann Arbor MI 48109. E-mail: jayhess@med.umich.edu.
The American Journal of Pathology, Vol. 175, No. 4, October 2009
Copyright © American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081142
tion of a number of bona fide tumor suppressors, includ-
ing RB, VHL, and BRCA1.
Recently, expression of po
tentially important micro-RNAs has also been shown to
be regulated by DNA.
Interestingly, many genes that
are mutated in familial cancers, such as BRCA1, are also
hypermethylated or deleted in sporadic cancer cases. In
addition, hypermethylation of some genes can promote
genomic instability. For example, the mismatch repair
gene MLH1 is hypermethylated in colorectal cancers as-
sociated with microsatellite instability.
DNA methylation is intimately associated with histone
modifications. Methyl CpG proteins such as MECP2,
MBD1, and MBD2, which specifically bind to CpG meth-
ylated DNA, are associated with histone deacetylase
(HDAC)-containing complexes so that they “erase” the
transcription-activating histone acetyl marks. Increasing
evidence indicates that patterns of repressive histone
methylation, specifically histone H3 lysine 27 methylation
established in stem cells, correlates with genes that are
commonly hypermethylated in cancer.
Histone Modifications
Histone Acetylation
Various mechanisms of histone modification may contribute
to epigenetic gene regulation. Histone tail acetylation at
lysine residues on histones H3 and H4 is associated with
transcriptional activation. Acetylation neutralizes the nega-
tive charge of DNA and generally renders DNA more ac-
cessible to transcription factors. In addition, histone acetyla-
tion creates marks that are “read” by chromatin-associated
proteins, many of which have evolutionarily conserved do-
mains, termed bromodomains, that selectively interact with
acetylated lysines. Experimentally, histone acetylation (and
other modifications such as methylation) are readily de-
tected by chromatin immunoprecipitation.
A wide variety of histone acetyltransferases (HATs)
have been identified, a number of which have been im-
plicated with aberrant transcriptional activation in cancer
Figure 1. Aberrant DNA methylation patterns in cancer cells as a result of
DNA methyltransferase overexpression. CpG dinucleotides are methylated in
normal cells, whereas CpG islands, consisting of overrepresented CpG clus-
ters near gene regulatory regions, are unmethylated. In contrast, cancer cells
generally show global hypomethylation with hypermethylation at CpG is-
lands, resulting in gene silencing at a subset of genes, including tumor
suppressor genes.
Table 1. Epigenetic Regulators Altered in Cancer
regulator class
regulator Function
modification Associated cancer Alteration in cancer
Writer DNMT1 DNMT Methyl CpG Various types Overexpressed
Writer DNMT3a DNMT Methyl CpG Various types Overexpressed
Writer DNMT3b DNMT Methyl CpG Various types Overexpressed
Writer p300 HAT Multiple lysines Leukemia,
Writer CBP HAT Multiple lysines Leukemia,
Writer MOZ HAT Multiple lysines Leukemia Translocation
Writer MORF HAT Multiple lysines Leukemia Translocation
Writer HDAC1-3, 6 HDAC General Various types Overexpressed
Writer RIZ1 HMT H3K9 Various types Down-regulation/mutation
Writer EZH2 HMT H3K27 Various types Overexpressed
Writer MLL1 HMT H3K4 Leukemia, lymphoma Translocation
Writer SMYD3 HMT H3K4 Colorectal, hepatocellular
Writer DOT1L HMT H3K79 Leukemia Deregulated recruitment
Writer NSD1 HMT H3K36 Leukemia, hepatocellular
Writer NSD2/MMSET HMT H3K36 Multiple myeloma Translocation
Writer NSD3 HMT H3K36 Breast cancer Translocation/overexpressed
Eraser JMJD2C/GASC1 Histone demethylase H3K9 Various types Overexpressed
Reader HP1 Methylated histone-binding
H3K9 Breast cancer, melanoma Down-regulation
Reader ING1-5 Methylated histone-binding
H3K4 Various types Down-regulation/mutation
Reader MBD1-4 Methyl-CpG-binding
Methyl CpG Various types Overexpressed
Reader MeCP2 Methyl-CpG-binding
Methyl CpG Various types Overexpressed
Remodeler INI1 SWI/SNF complex Malignant rhabdoid tumor Inactivating mutations
Remodeler BRM SWI/SNF complex Various types Inactivating mutations
Remodeler BRG1 SWI/SNF complex Various types Inactivating mutations
Remodeler ATRX SWI/SNF complex Myelodysplasia Inactivating mutations
1354 Muntean and Hess
AJP October 2009, Vol. 175, No. 4
(Table 1). The HATs are, in turn, modulated by a number
of HDACs, which fall into three general classes: class I
HDACs, which are homologous to yeast Rpd3, class II
HDACs, which are homologous to yeast Hda1, and class
III HDACs, which are distinguished by their dependence
on NAD
. HDAC inhibitors are finding increasing clinical
applications. As is a general theme with histone-modify-
ing enzymes, a number of nonhistone substrates have
been identified, including proteins important for carcino-
genesis, such as p53, GATA-1, and E2F1.
14 –16
Histone Methylation
Whereas histone acetylation is highly dynamic, modifica-
tion of histones by mono-, di-, and trimethylation of lysine
residues, both in the histone tail as well as core nucleo-
somes, is thought to be a more lasting modification that
comprises a form of “cellular memory.” Studies of Dro-
sophila have identified two groups of proteins that are
associated with either transcriptional maintenance or
repression that are termed Trithorax or Polycomb group
proteins, respectively. Several Trithorax proteins, most
notably the mixed lineage leukemia protein MLL, are
histone H3 lysine 4 methyltransferases. In contrast, Poly-
comb group proteins such as EZH2 have histone H3
lysine 27 methyltransferase activity, which plays impor-
tant roles in silencing at euchromatic regions as well as in
maintenance of heterochromatic regions in association
with histone H3 lysine 9 methylation.
Recently, a number of “readers” of methylated histone
tails have been identified. One group of these proteins
contains chromodomains, which recognize histones
methylated on lysine 9 or 27. One possible role for these
chromodomain- containing proteins is to target Polycomb
repression complexes to sites of transcriptional regula-
tion and DNA replication. The latter has been implicated
as a possible means of perpetuating the lysine 27 methyl
mark during DNA replication.
Although it is clear that histone methylation is involved
in establishing long-term patterns of gene expression, it
is increasingly apparent that this modification is also
dynamic. Indeed, a variety of histone demethylases, in-
cluding LSD1 and the jumonji family of proteins,
been identified.
Other Histone Modifications
Replacement of modified histones with unmodified or
variant histones is another possible mechanism of chang-
ing expression patterns.
Interestingly, proteolytic cleav
age of histone tails has also been recognized as a mech-
anism for “erasing” histone modifications.
Like HATs,
histone methyltransferases (HMTs) have activity on a va-
riety of nonhistone substrates, such as p53, which may
have important cancer implications.
Further adding to the complexity of posttranslational
modifications, histones undergo a variety of other modi-
fications, including phosphorylation, sumoylation, and
ubiquitination. Histone monoubiquitination (as opposed
to polyubiquitination, which is associated with proteoso-
mal degradation) occurs not on tails but on the core
histones H2A at lysine 119 (mediated by RING1A) and
H2B on lysine 123 (mediated by BRE1/RAD6). These
modifications are required for the subsequent methyl-
ation at lysine 27 and lysines 4 and 79, respectively.
Disruption of “Writers,” “Readers,” and
“Erasers” of the Histone Code in Cancer
Ample evidence suggests that the “histone code” is de-
ranged in cancer. For example, cancer cells commonly
show loss of lysine 16 acetylation and lysine 20 methyl-
Furthermore, global changes in histone acetyla
tion and methylation are seen in cancer cells when com-
pared with normal cells, and these changes can be used
to predict disease outcome in tumors such as prostate
For example, differentiation of embryonic stem
cells is accompanied by the appearance of large regions
of H3K9-dimethylated chromatin (4 Mb) termed LOCKs.
LOCKs are common in differentiated tissues such as liver
and brain and have been found to be dramatically reduced
in cancer cell lines.
Heterochomatin Protein 1
In recent years, a number of readers, writers and erasers
of the histone code have been implicated in carcinogen-
esis. Heterochromatin protein 1 (HP1) is a good example
of a histone reader that is disrupted in cancer. The HP1
family, which is composed of HP1
(CBX5), HP1
(CBX1) and HP1
(CBX3), plays an integral role in main-
taining silenced heterochromatin. All three family mem-
bers specifically bind histone H3 that is methylated on
lysine 9 (H3K9), a transcriptionally repressive modifica-
tion associated with heterochromatin and silenced eu-
HP1 is targeted to methylated H3K9 via the
This mark is deposited by several pro
teins, including the Suppressor of variegation, Enhancer
of Zeste and Trithorax (SET) domain HMT SUV39H1.
HP1 dimerization results in recruitment of other H3K9
HMTs, leading to additional HP1 recruitment.
HP1 re
cruitment of Suv4-20 HMTs and the Dnmt3a/3b DNA
methyltransferases establishes a complete transcription-
ally repressed state.
is localized to silenced euchromatic sites, and
and HP1
are localized to pericentric chromatin.
Loss of HP1 function results in kinetochore defects, de-
fective chromosome condensation and segregation, and
impaired telomere function. HP1 down-regulation has
been noted in metastatic breast cancer, papillary thyroid
carcinoma, and medulloblastoma.
Strikingly, overex
pression of HP1 in metastatic breast cancer cells de-
creased invasiveness, whereas knockdown of HP1 in
nonmetastatic cells increased invasiveness, suggesting
HP1 functions as a metastasis suppressor.
Frame shift,
missense mutations, and epigenetic silencing also con-
tribute to HP1 down-regulation, allowing for cancer pro-
HP1 is also recruited to the cell cycle control
gene, cyclin E, indicating a direct link to cell proliferation
following HP1 inhibition.
As noted above, chromosome
Epigenetic Dysregulation in Cancer 1355
AJP October 2009, Vol. 175, No. 4
instability, including aneuploidy and telomere fusion, results
from reduction or overexpression of HP1, respectively.
Thus, down-regulation of HP1 in cancer likely contributes to
tumor progression by leading to aneuploidy of other chro-
mosomal abnormalities.
Inhibitor of Growth 1
The inhibitor of growth (ING) protein ING1 is another
reader of the histone code that was discovered through a
candidate tumor suppressor screen using cDNA from
normal and breast cancer cell lines (Figure 2A).
sequent phylogenetic analysis revealed four more mem-
bers of the ING family, ING2–5.
Consistent with their
role as putative tumor suppressors, ING proteins interact
with p53 to induce apoptosis, cellular senescence, and
growth arrest.
ING proteins also associate with a large
chromatin-remodeling complex that includes HDAC1,
Sin3a, and SAP30,
which functions as a general
repressor of transcription.
The domain required for in
teraction with Sin3-HDAC is essential for ING-dependent
cell cycle arrest.
All ING proteins share a plant homeodomain (PHD),
which preferentially binds di- and tri-methylated H3K4.
The PHD finger of ING2 also interacts with phosphatidylino-
sitol-5-phosphate, aiding in ING2 localization to chroma-
Mutations detected within the PHD finger result in
premature stop codons or disrupted Zn
coordination and
improper folding of the domain.
This likely disrupts ING
binding to methylated H3K4, resulting in improper regula-
tion of target genes such as p21 and cyclin B1, which are
thought to be important for tumorigenesis in cells with ING
These mutations have been described in
breast cancer, melanoma, head and neck and esophageal
squamous cell carcinoma.
Similarly, nuclear localization
signal mutations lead to ING exclusion from the nucleus and
have been found in brain and breast tumors, as well as
melanoma and lymphoblastic leukemia.
Additionally, ING
proteins have been found to be down-regulated by either
loss of heterozygosity or promoter hypermethylation in a
variety of tumors, including breast, gastric, esophageal,
blood, lung, and brain cancers.
Reduction of expres
sion of ING1 has been noted in 50% of cases of head and
neck cancer and esophageal squamous cell carcinoma
and 25% of ovarian cancers.
Mixed Lineage Leukemia
The Mixed Lineage Leukemia (MLL) gene is rearranged in
human lymphoid and myeloid acute leukemias (Figure
MLL is an example of a histone code writer; MLL
has HMT activity specific for histone H3K4 that is medi-
ated by its carboxyl terminal SET domain
Mll knock
out mice are embryonic lethal at day E10.5 and show
defects of the axial skeleton and hematopoietic system
that are accompanied by defects in HOX gene expres-
sion and histone H3K4 methylation.
Translocations in
volving MLL result in fusion of N-terminal sequences of
MLL up to and including a DNA methyltransferase homol-
ogy (CXXC) domain to one of 60 translocation partners.
Figure 2. Disruption of histone readers, writers, and erasers in cancer.
A: ING proteins use PHD fingers to recognize the trimethylated histone
H3K4. Cell cycle arrest is mediated by the ING protein binding to prolif-
erative genes, such as cyclins, and recruitment of HDAC complexes that
deacetylate histone tails, resulting in gene silencing. Inactivating muta-
tions or down-regulation of ING proteins results in deregulated cyclin
expression and proliferation. B: MLL is a histone H3K4 methyltransferase
that is required for maintenance of HOX gene expression. MLL translo-
cations interact with various partners, including AF4, leading to the
aberrant recruitment of the histone H3K79 methyltransferase Dot1. Dot1-
mediated methylation at H3K79 results in deregulated expression of HOX
genes, which are critical for transformation. Other proteins recruited by
MLL fusion proteins that may also play a role in transcriptional activity are
not shown. C: JMJD2C normally functions to demethylate H3K9, leading
to transcriptional activation. In cancers that overexpress JMJD2C, a global
reduction in H3K9 is observed, resulting in demethylation and increased
expression of target genes such as self renewal genes, which likely
contribute to tumorigenesis.
1356 Muntean and Hess
AJP October 2009, Vol. 175, No. 4
These translocations consistently delete the more C ter-
minal PHD fingers, which have been shown to inhibit
Despite deletion of the SET domain, MLL fusion pro-
teins potently up-regulate target genes, including HOXA7,
HOXA9, and the HOX cofactor MEIS1, which are essential
for MLL fusion protein-mediated transformation.
transcriptional activation appears to be mediated via re-
cruitment of a complex containing multiple MLL translo-
cation partners, including AF4, AF5q31, and LAF4, in
addition to two proteins with enzymatic activity that stim-
ulate transcriptional elongation: CDK9, which together
with cyclin T1 or 2 comprises the pTEFb complex, and
DOT1L, a histone H3 lysine 79-specific HMT
that has
previously been shown to interact with the MLL translo-
cation partner AF10 (Figure 2B).
Histone H3 K79 meth
ylation is associated with active transcription.
ingly, MLL rearranged leukemias show abnormally high
lysine 79 methylation that is broadly distributed across
the HOXA and MEIS1 loci.
Preliminary experiments sug
gest that inhibition of DOT1 methyltransferase activity
inhibits HOX expression and the growth of cells with MLL
rearrangements. Although DOT1 specificity for MLL-rear-
ranged leukemias remains to be established, these data
suggest that DOT1 may be a promising therapeutic
Enhancer of Zeste 2
Enhancer of Zeste (EZH2), a member of the Polycomb
group of proteins, is another histone code writer that is
disrupted in cancer. EZH2 has intrinsic histone H3K27
methyltransferase activity and assembles into a multipro-
tein complex termed Polycomb repressive complex 2
(PRC2), which consists of EZH2, the WD40 repeat protein
EED, and the zinc finger protein SUZ12.
The methyl
ation of histone H3 lysine 27 catalyzed by this complex is
recognized by a second Polycomb complex, PRC1, which
is primarily composed of HPC, HPH, RING1, and BMI1;
PRC1 binds and maintains a state of transcriptional repres-
Collectively, these complexes inhibit expression
of a variety of proteins including the HOX genes and thereby
antagonize the activity of Trithorax group proteins such as
It has been reported that DNMTs and HDACs, such
as SIRT1, are recruited by the PRC2 complex and contrib-
ute to gene silencing,
thereby linking two major silencing
pathways: histone H3 lysine 27 methylation and DNA meth-
ylation. However, the recent report
that EZH2 down-reg
ulation restores expression of H3K27-targeted genes with-
out affecting DNA methylation raises questions about the
significance of DNA methylation in Polycomb-mediated
Up-regulation of EZH2 is seen in a number of tumor
types, including lymphomas, prostate cancer, and breast
cancer, where the expression level appears to correlate
with disease progression.
EZH2 may contribute to
cancer progression by maintaining a stem cell-like phe-
notype. Overexpression of EZH2 has been shown to pre-
vent exhaustion of hematopoietic stem cells in serially
transplanted mice, and ES cell lines cannot be estab-
lished from Ezh2
Importantly, a
causal link between EZH2 and cancer was established
when it was shown that overexpression of EZH2 in the
B-cell-derived Ramos cell line or multiple myeloma cells
caused increased proliferation.
Conversely, differen
tiation of the promyelocytic HL60 cell line results in down-
regulation of EZH2. Furthermore, RNA interference-medi-
ated knockdown of EZH2 causes growth arrest at the
-M phase in prostate cells and suppression of DNA
synthesis in HL60 cells.
Importantly, the HMT activity
of EZH2 and the deacetylase activity of EED-recruited
HDACs are necessary for EZH2-mediated cell prolifera-
tion and target gene repression.
EZH2 mRNA and protein levels are low in benign pros-
tate and increase progressively from localized to metastatic
tumors, suggesting EZH2 could be a useful prognostic
indicator as well as a potential therapeutic target.
estingly, EZH2 expression is regulated by micro-RNA-101,
which is encoded by a locus that is commonly deleted in
prostate cancer. The miR-101 locus is deleted at one or
both loci in 37.5% of clinically localized prostate cancer and
66.7% of metastatic prostate tumors, suggesting loss
of micro-RNA-101 leads to EZH2 overexpression and
cancer progression mediated by deregulated epige-
netic mechanisms.
Jumonji Domain Containing 2C
Jumonji domain containing 2C (JMJD2C), also known as
GASC1, is one of a family of three histone demethylases
(including JMJD2A and JMJD2B) that is amplified in a
variety of cancers and functions as erasers of the histone
code (Figure 2C).
The jumonji domain family is charac
Figure 3. SWI/SNF-mediated nucleosomal remodeling and transcription in
cancer. BRG1 is a DNA-dependent protein that functions in a SWI/SNF
complex, which can remodel histones in several ways to make transcriptional
start sites more accessible to transcription machinery. For example, SWI/SNF
complexes allow histones to “slide” along DNA to expose DNA sequences as
well as allow DNA looping away from histones to increase accessibility.
BRG1 can also recruit pRb to regulate E2F target genes. Mutations in BRG1 in
cancer inhibit the function of SWI/SNF complexes resulting to deregulated
Epigenetic Dysregulation in Cancer 1357
AJP October 2009, Vol. 175, No. 4
terized by the presence of the jumonji domain, which is
the catalytically active histone demethylase. The jumonji
domain in JMJD2C is specific for di- and trimethylated
histone H3 lysine 9.
JMJD2C overexpression dramati
cally reduces histone H3 lysine 9 methylation, resulting in
delocalization of HP-1 and thereby impairing heterochro-
matin formation.
Considerable insights into JMJD2
function have come from studies of embryonic stem cell
differentiation, which is accompanied by widespread in-
creases in histone H3 lysine 9 methylation. Oct4, one of
the key transcription factors involved in maintaining embry-
onic stem cell self-renewal, regulates JMJD2 expression,
which in turn regulates expression of Nanog, another tran-
scription factor critical for stem cell maintenance. Further-
more, depletion of JMJD2C or JMJD2A results in embryonic
stem cell differentiation, suggesting that JMJD2 promotes
stem cell self-renewal.
JMJD2 overexpression has been reported in a number
of human tumors, including esophageal squamous cell
carcinoma, desmoplastic medulloblastoma, and occa-
sional cases of MALT lymphoma, the latter as a result of
chromosomal translocation with the IgH locus.
82– 84
sistent with its role as an oncoprotein, inhibition of
JMJD2C expression in esophageal carcinoma or U2OS
osteosarcoma cells results in decreased proliferation.
Chromatin Remodeling
The nucleosome presents a barrier to transcription factor
binding as well as transcriptional elongation. A variety of
evolutionarily conserved mechanisms exist to overcome
this, most notably the SWItch/Sucrose NonFermentable
(SWI/SNF) ATP-dependent chromatin remodeling com-
Perhaps through promoting chromatin accessibil
ity to both coactivators and repressors through nucleo-
some displacement or through DNA displacement from
nucleosomes, the SWI/SNF complex has both positive or
repressive effects on transcription depending on chro-
matin context.
Determining the precise role of chroma
tin remodeling in cancer has been somewhat hampered
by the relatively difficult and insensitive testing methods
available, which use DNase hypersensitivity and South-
ern blot analysis for assessing nucleosomal position
(phasing) in tumor tissues.
Perhaps the best studied example of chromatin-re-
modeling enzyme disruptions in cancer is the loss of
expression of the INI1 (SNF5/SMARCB1/BAF47), a core
component of the SWI/SNF complex, in malignant rhab-
doid tumors as well as other primitive undifferentiated
pediatric sarcomas. This aggressive tumor of childhood
appears to be the result of deregulation of multiple onco-
genic pathways, including cyclin D1 up-regulation.
Mutations have also been identified in the BRG1 ATPase of
the SWI/SNF complex in a variety of solid tumors, including
lung, prostate, pancreas, colorectal, and breast carcinoma,
among others.
BRG1 interacts with Rb, so it has been
postulated that BRG1 mutations disrupt the ability of Rb to
act as a tumor suppressor (Figure 3).
In addition, con
stitutional mutations of ATRX, a SNF2 family chromatin re-
modeling protein, are associated with a variety of develop-
mental abnormalities, including facial dysmorphism, mental
retardation, and
Acquired mutations of
ATRX are associated with the
thalassemia myelodysplas-
tic syndrome. As further evidence of the interplay between
different epigenetic modifications, ATRX mutations are also
associated with abnormal patterns of DNA methylation.
Implications for Therapy
Success with the development of kinase inhibitors such
as imatinib in CML therapy raises hopes that epigenetic
regulators may also be attractive therapeutic targets.
Currently, two types of epigenetic-based therapies have
made their way into clinical use, HDAC inhibitors (HDACi)
and inhibitors of DNA methyltransferases.
Tumor cells
generally show higher sensitivity to HDACi than normal
HDACi have shown particular efficacy against
cutaneous T cell lymphomas and one, suberoylanilide
hydroxamic acid (vorinostat), has been Food and Drug
Administration approved for this application.
The mecha
nisms through which HDACi inhibit growth or kill tumor
cells, however, remains unclear. Although HDACi can
inhibit tumor growth through the up-regulation of the cy-
clin-dependent kinase inhibitor p21, many other mecha-
nisms of HDACi action have been identified, including
inhibiting DNA repair mechanisms and acetylating non-
histone proteins.
A number of HDAC inhibitors, includ
ing valproic acid, vorinostat, depsipeptide, and many
others are currently in clinical trials for solid tumors with
generally mixed results.
The inhibitors of DNMT in most wide clinical use are
nucleoside analogs that get converted to dNTPs and
become incorporated into DNA in place of cytosine dur-
ing DNA replication. Of these, 5-azacytidine received
Food and Drug Administration approval for myelodys-
plastic disorders and leukemia in 2004
and decitabine
(5-Aza-2-deoxcytidine) in 2006.
These inhibitors, and
many others such as zebularine, 5-fluoro-2-deoxycyti-
dine, and 5,6-dihydro-5-azacytidine, are currently in clin-
ical trials for a wide range of hematological malignancies
and for solid tumors, where their efficacy in general has
been less.
In addition, some studies suggest the com
bination of HDAC and DNA methylation inhibitors for
cancer therapy are more effective than either agent
One of the biggest concerns with current epigenetic
regulators is their nonspecific effects. Induction of global
hypomethylation, for example, has the potential to acti-
vate other oncogenes as well as induce additional
genomic instability. HDAC inhibitors have many “off tar-
get” effects that contribute to their toxicity. It is likely that
additional inhibitors will be developed that target specific
HMTs such as EZH2 or DOT1. Alternatively, inhibitors
might be developed to inhibit DNA or histone recognition
modules such as CXXC or PHD domains.
Another exciting possibility is the use of epigenetic
modifiers to induce tumor antigens that can then be used
as targets for cancer immunotherapy. Cancer testis anti-
gens as an example are normally expressed in male
germ cells. Cancer testis antigens are generally highly
1358 Muntean and Hess
AJP October 2009, Vol. 175, No. 4
immunogenic and, when reactivated by DNA demethyl-
ating agents, show promise when combined with cancer
Similar approaches are being ex
plored to restore hormone sensitivity such as reinducing
immunotherapy, thereby targeting reactivated estrogen
receptor re-expression in conjunction with tamoxifen
1. Holliday R: The inheritance of epigenetic defects. Science 1987,
2. Esteller M: Epigenetics in cancer. N Engl J Med 2008, 358:1148 –1159
3. Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M,
Tackett AJ, Chait BT, Badenhorst P, Wu C, Allis CD: A PHD finger of
NURF couples histone H3 lysine 4 trimethylation with chromatin re-
modelling. Nature 2006, 442:86 –90
4. Feinberg A, Tycko B: The history of cancer epigenetics. Nat Rev
Cancer 2004, 4:143–153
5. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M,
Burton J, Cox TV, Davies R, Down TA, Haefliger C, Horton R, Howe K,
Jackson DK, Kunde J, Koenig C, Liddle J, Niblett D, Otto T, Pettett R,
Seemann S, Thompson C, West T, Rogers J, Olek A, Berlin K, Beck S:
DNA methylation profiling of human chromosomes 6, 20 and 22. Nat
Genet 2006, 38:1378–1385
6. Feinberg A, Vogelstein B: Hypomethylation distinguishes genes of
some human cancers from their normal counterparts. Nature 1983,
301:89 –92
7. Gal-Yam EN, Saito Y, Egger G, Jones PA: Cancer epigenetics: mod-
ifications, screening, and therapy. Annu Rev Med 2008, 59:267–280
8. Cui H, Cruz-Correa M, Giardiello FM, Hutcheon DF, Kafonek DR,
Brandenburg S, Wu Y, He X, Powe NR, Feinberg AP: Loss of IGF2
imprinting: a potential marker of colorectal cancer risk. Science 2003,
9. Teodoridis JM, StrathdeeG, Brown R: Epigenetic silencing mediated
by CpG island methylation: potential as a therapeutic target and as a
biomarker. Drug Resist Updat 2004, 7:267–278
10. Baylin SB, Ho¨ppener JW, de Bustros A, Steenbergh PH, Lips CJ,
Nelkin BD: DNA methylation patterns of the calcitonin gene in human
lung cancers and lymphomas. Cancer Res 1986, 46:2917–2922
11. Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA,
Jones PA: Specific activation of microRNA-127 with downregulation
of the proto-oncogene BCL6 by chromatin-modifying drugs in human
cancer cells. Cancer Cell 2006, 9:435– 443
12. Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP: Loss of
imprinting in normal tissue of colorectal cancer patients with micro-
satellite instability. Nat Med 1998, 4:1276 –1280
13. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N,
Strouboulis J, Wolffe AP: Methylated DNA and MeCP2 recruit histone
deacetylase to repress transcription. Nat Genet 1998, 19:187–191
14. Boyes J, Byfield P, Nakatani Y, Ogryzko V: Regulation of activity of the
transcription factor GATA-1 by acetylation. Nature 1998, 396:594 –598
15. Luo J, Li M, Tang Y, Laszkowska M, Roeder RG, Gu W: Acetylation of
p53 augments its site-specific DNA binding both in vitro and in vivo.
Proc Natl Acad Sci USA 2004, 101:2259 –2264
16. Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T:
Regulation of E2F1 activity by acetylation. EMBO J 2000, 19:662– 671
17. Hansen KH, Bracken AP, Pasini D, Dietrich N, Gehani SS, Monrad A,
Rappsilber J, Lerdrup M, Helin K: A model for transmission of the
H3K27me3 epigenetic mark. Nat Cell Biol 2008, 10:1291–1300
18. Agger SA, Lopez-Gallego F, Hoye TR, Schmidt-Dannert C: Identification
of sesquiterpene synthases from Nostoc punctiforme PCC 73102 and
Nostoc strain PCC 7120. J Bacteriol 2008, 190:6084 6096
19. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero
RA, Shi Y: Histone demethylation mediated by the nuclear amine
oxidase homolog LSD1. Cell 2004, 119:941–953
20. Bernstein E, Hake SB: The nucleosome: a little variation goes a long
way. Biochem Cell Biol 2006, 84:505–517
21. Duncan EM, Muratore-Schroeder TL, Cook RG, Garcia BA,
Shabanowitz J, Hunt DF, Allis CD: Cathepsin L proteolytically processes
histone H3 during mouse embryonic stem cell differentiation. Cell 2008,
135:284 –294
22. Sims RJ III, Reinberg D: Is there a code embedded in proteins that is
based on post-translational modifications? Nat Rev Mol Cell Biol
2008, 9:815– 820
23. Bhaumik SR, Smith E, Shilatifard A: Covalent modifications of histones
during development and disease pathogenesis. Nat Struct Mol Biol
2007, 14:1008 –1016
24. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J,
Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Pe´rez-
Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris
MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M: Loss of
acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a
common hallmark of human cancer. Nat Genet 2005, 37:391– 400
25. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani
SK: Global histone modification patterns predict risk of prostate can-
cer recurrence. Nature 2005, 435:1262–1266
26. Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP: Large histone H3
lysine 9 dimethylated chromatin blocks distinguish differentiated from
embryonic stem cells. Nat Genet 2009, 41:246 –250
27. Grewal SI, Jia S: Heterochromatin revisited. Nat Rev Genet 2007,
8:35– 46
28. Jacobs SA, Khorasanizadeh S: Structure of HP1 chromodomain
bound to a lysine 9-methylated histone H3 tail. Science 2002,
295:2080 –2083
29. Dillon SC, Zhang X, Trievel RC, Cheng X: The SET-domain protein
superfamily: protein lysine methyltransferases. Genome Biol 2005,
30. Cowieson NP, Partridge JF, Allshire RC, McLaughlin PJ: Dimerisation
of a chromo shadow domain and distinctions from the chromodomain
as revealed by structural analysis. Curr Biol 2000, 10:517–525
31. Moss TJ, Wallrath LL: Connections between epigenetic gene silenc-
ing and human disease. Mutat Res 2007, 618:163–174
32. Wang GG, Allis CD, Chi: Chromatin remodeling and cancer—Part I:
covalent histone modifications. Trends Mol Med 2007, 13:363–372
33. Norwood LE, Moss TJ, Margaryan NV, Cook SL, Wright L, Seftor EA,
Hendrix MJ, Kirschmann DA, Wallrath LL: A requirement for dimer-
ization of HP1Hs
in suppression of breast cancer invasion. J Biol
Chem 2006, 281:18668–18676
34. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O’Carroll
D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T: Rb
targets histone H3 methylation and HP1 to promoters. Nature 2001,
35. Garkavtsev I, Kazarov A, Gudkov A, Riabowol K: Suppression of the
novel growth inhibitor p33ING1 promotes neoplastic transformation.
Nat Genet 1996, 14:415– 420
36. He GH, Helbing CC, Wagner MJ, Sensen CW, Riabowol K: Phyloge-
netic analysis of the ING family of PHD finger proteins. Mol Biol Evol
2005, 22:104 –116
37. Shi X, Gozani O: The fellowships of the INGs. J Cell Biochem 2005,
38. Kuzmichev A, Zhang Y, Erdjument-Bromage H, Tempst P, Reinberg
D: Role of the Sin3-histone deacetylase complex in growth regulation
by the candidate tumor suppressor p33(ING1). Mol Cell Biol 2002,
22:835– 848
39. Doyon Y, Cayrou C, Ullah M, Landry AJ, Coˆte´ V, Selleck W, Lane WS,
Tan S, Yang XJ, Coˆte´ J: ING tumor suppressor proteins are critical
regulators of chromatin acetylation required for genome expression
and perpetuation. Mol Cell 2006, 21:51– 64
40. Skowyra D, Zeremski M, Neznanov N, Li M, Choi Y, Uesugi M, Hauser
CA, Gu W, Gudkov AV, Qin J: Differential association of products of
alternative transcripts of the candidate tumor suppressor ING1 with
the mSin3/HDAC1 transcriptional corepressor complex. J Biol Chem
2001, 276:8734 8739
41. Pen˜a PV, Davrazou F, Shi X, Walter KL, Verkhusha VV, Gozani O, Zhao
R, Kutateladze TG: Molecular mechanism of histone H3K4me3 recog-
nition by plant homeodomain of ING2. Nature 2006, 442:100 –103
42. Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T, Carney D,
Pen˜ a P, Lan F, Kaadige MR, Lacoste N, Cayrou C, Davrazou F, Saha
A, Cairns BR, Ayer DE, Kutateladze TG, Shi Y, Coˆte´ J, Chua KF,
Gozani O: ING2 PHD domain links histone H3 lysine 4 methylation to
active gene repression. Nature 2006, 442:96 –99
43. Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA,
Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen
Epigenetic Dysregulation in Cancer 1359
AJP October 2009, Vol. 175, No. 4
J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG,
Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J: The PHD
finger of the chromatin-associated protein ING2 functions as a nu-
clear phosphoinositide receptor. Cell 2003, 114:99 –111
44. Baker LA, Allis CD, Wang GG: PHD fingers in human diseases:
disorders arising from misinterpreting epigenetic marks. Mutat Res
2008, 647:3–12
45. Gong Y, Sohn H, Xue L, Firestone GL, Bjeldanes LF: 3,3-Diindolyl-
methane is a novel mitochondrial H-ATP synthase inhibitor that can
induce p21(Cip1/Waf1) expression by induction of oxidative stress in
human breast cancer cells. Cancer Res 2006, 66:4880 4887
46. Takahashi M, Seki N, Ozaki T, Kato M, Kuno T, Nakagawa T,
Watanabe K, Miyazaki K, Ohira M, Hayashi S, Hosoda M, Tokita H,
Mizuguchi H, Hayakawa T, Todo S, Nakagawara A: Identification of the
p33(ING1)-regulated genes that include cyclin B1 and proto-oncogene
DEK by using cDNA microarray in a mouse mammary epithelial cell line,
NMuMG. Cancer Res 2002, 62:2203–2209
47. Ythier D, Larrieu D, Brambilla C, Brambilla E, Pedeux R: The new
tumor suppressor genes ING: genomic structure and status in can-
cer. Int J Cancer 2008, 123:1483–1490
48. Coles AH, Jones SN: The ING gene family in the regulation of cell
growth and tumorigenesis. J Cell Physiol 2008, 218:45–57
49. Gunduz M, Ouchida M, Fukushima K, Hanafusa H, Etani T, Nishioka
S, Nishizaki K, Shimizu K: Genomic structure of the human ING1 gene
and tumor-specific mutations detected in head and neck squamous
cell carcinomas. Cancer Res 2000, 60:3143–3146
50. Shen DH, Chan KY, Khoo US, Ngan HY, Xue WC, Chiu PM, Ip P,
Cheung AN: Epigenetic and genetic alterations of p33ING1b in ovar-
ian cancer. Carcinogenesis 2005, 26:855–863
51. Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R III, Patel Y,
Harden A, Rubinelli P, Smith SD, LeBeau MM, Rowley JD: Identifica-
tion of a gene MLL, that spans the breakpoint in 11q23 translocations
associated with human leukemias. Proc Natl Acad Sci USA 1991,
52. Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess
JL: MLL targets SET domain methyltransferase activity to Hox gene
promoters. Mol Cell 2002, 10:1107–1117
53. Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R,
Dubois G, Mazo A, Croce CM, Canaani E: ALL-1 is a histone meth-
yltransferase that assembles a supercomplex of proteins involved in
transcriptional regulation. Mol Cell 2002, 10:1119 –1128
54. Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ: Altered Hox
expression and segmental identity in Mll-mutant mice. Nature 1995,
55. Hess JL: MLL: a histone methyltransferase disrupted in leukemia.
Trends Mol Med 2004, 10:500–507
56. Muntean AG, Giannola D, Udager AM, Hess JL: The PHD fingers of
MLL block MLL fusion protein-mediated transformation. Blood 2008,
112:4690 4693
57. Chen J, Santillan DA, Koonce M, Wei W, Luo R, Thirman MJ,
Zeleznik-Le NJ, Diaz MO: Loss of MLL PHD finger 3 is necessary for
MLL-ENL-induced hematopoietic stem cell immortalization. Cancer
Res 2008, 68:61996207
58. Ayton PM, Cleary ML: Transformation of myeloid progenitors by MLL
oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev 2003,
17:2298 –2307
59. Mueller D, Bach C, Zeisig D, Garcia-Cuellar MP, Monroe S, Sreekumar
A, Zhou R, Nesvizhskii A, Chinnaiyan A, Hess JL, Slany RK: A role for the
MLL fusion partner ENL in transcriptional elongation and chromatin
modification. Blood 2007, 110:4445– 4454
60. Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang
Y: hDOT1L links histone methylation to leukemogenesis[erratum ap-
pears in Cell 2005, 121:809]. Cell 2005, 121:167–178
61. Shilatifard A: Chromatin modifications by methylation and ubiquitination:
implications in the regulation of gene expression. Annu Rev Biochem
2006, 75:243–269
62. Milne TA, Martin ME, Brock HW, Slany RK, Hess JL: Leukemogenic
MLL fusion proteins bind across a broad region of the Hox a9 locus,
promoting transcription and multiple histone modifications. Cancer
Res 2005, 65:11367–11374
63. Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, Xia X,
Jesneck J, Bracken AP, Silverman LB, Kutok JL, Kung AL, Armstrong
SA: H3K79 methylation profiles define murine and human MLL-AF4
leukemias. Cancer Cell 2008, 14:355–368
64. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg
D: Histone methyltransferase activity associated with a human multi-
protein complex containing the enhancer of Zeste. Protein Genes Dev
2002, 16:2893–2905
65. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P,
Jones RS, Zhang Y: Role of histone H3 lysine 27 methylation in
Polycomb-group silencing. Science 2002, 298:1039–1043
66. Fischle W, Wang Y, Jacobs SA, Kim Y, Allis CD, Khorasanizadeh S:
Molecular basis for the discrimination of repressive methyl-lysine
marks in histone H3 by Polycomb and HP1 chromodomains. Genes
Dev 2003, 17:1870–1881
67. Min J, Zhang Y, Xu RM: Structural basis for specific binding of
Polycomb chromodomain to histone H3 methylated at Lys 27. Genes
Dev 2003, 17:1823–1828
68. Sparmann A, van Lohuizen M: Polycomb silencers control cell fate,
development and cancer. Nat Rev Cancer 2006, 6:846 856
69. Vire´ E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey
L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M,
Di Croce L, de Launoit Y, Fuks F: The Polycomb group protein EZH2
directly controls DNA methylation. Nature 2006, 439:871– 874
70. Kondo Y, Shen L, Cheng AS, Ahmed S, Boumber Y, Charo C, Yamochi
T, Urano T, Furukawa K, Kwabi-Addo B, Gold DL, Sekido Y, Huang TH,
Issa JP: Gene silencing in cancer by histone H3 lysine 27 trimethy-
lation independent of promoter DNA methylation. Nat Genet 2008,
71. Visser HP, Gunster MJ, Kluin-Nelemans HC, Manders EM, Raaphorst
FM, Meijer CJ, Willemze R, Otte AP: The Polycomb group protein
EZH2 is upregulated in proliferating, cultured human mantle cell
lymphoma. Br J Haematol 2001, 112:950 –958
72. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha
C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA,
Chinnaiyan AM: The polycomb group protein EZH2 is involved in
progression of prostate cancer. Nature 2002, 419:624 629
73. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O,
Haukaas SA, Salvesen HB, Otte AP, Akslen LA: EZH2 expression is
associated with high proliferation rate and aggressive tumor sub-
groups in cutaneous melanoma and cancers of the endometrium,
prostate, and breast. J Clin Oncol 2006, 24:268–273
74. Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing
E, Dontje B, de Haan G: The Polycomb group gene Ezh2 prevents
hematopoietic stem cell exhaustion. Blood 2006, 107:2170 –2179
75. O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T:
The polycomb-group gene Ezh2 is required for early mouse devel-
opment. Mol Cell Biol 2001, 21:4330 4336
76. Croonquist PA, Van Ness B: The polycomb group protein enhancer of
zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell
growth and the mutant ras phenotype. Oncogene 2005, 24:6269 6280
77. Fukuyama T, Otsuka T, Shigematsu H, Uchida N, Arima F, Ohno Y,
Iwasaki H, Fukuda T, Niho Y: Proliferative involvement of ENX-1, a
putative human polycomb group gene, in haematopoietic cells. Br J
Haematol 2000, 108:842–847
78. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B,
Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan
P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan
AM: Genomic loss of microRNA-101 leads to overexpression of histone
methyltransferase EZH2 in cancer. Science 2008, 322:1695–1699
79. Katoh M: Identification and characterization of JMJD2 family genes in
silico. Int J Oncol 2004, 24:1623–1628
80. Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T,
Hansen KH, Helin K: The putative oncogene GASC1 demethylates tri-
and dimethylated lysine 9 on histone H3. Nature 2006, 442:307–311
81. Loh YH, Zhang W, Chen X, George J, Ng HH: Jmjd1a and Jmjd2c
histone H3 Lys 9 demethylases regulate self-renewal in embryonic
stem cells. Genes Dev 2007, 21:2545–2557
82. Ehrbrecht A, Mu¨ller U, Wolter M, Hoischen A, Koch A, Radlwimmer B,
Actor B, Mincheva A, Pietsch T, Lichter P, Reifenberger G, Weber RG:
Comprehensive genomic analysis of desmoplastic medulloblastomas:
identification of novel amplified genes and separate evaluation of the
different histological components. J Pathol 2006, 208:554 –563
83. Italiano A, Attias R, Aurias A, Pe´rot G, Burel-Vandenbos F, Otto J,
Venissac N, Pedeutour F: Molecular cytogenetic characterization of a
metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and
9p23–p24 amplification including JAK2 and JMJD2C. Cancer Genet
Cytogenet 2006, 167:122–130
1360 Muntean and Hess
AJP October 2009, Vol. 175, No. 4
84. Vinatzer U, Gollinger M, Mu¨llauer L, Raderer M, Chott A, Streubel B:
Mucosa-associated lymphoid tissue lymphoma: novel translocations
including rearrangements of ODZ2. JMJD2C, and CNN3. Clin Cancer
Res 2008, 14:64266431
85. Roberts CW, Orkin SH: The SWI/SNF complex—chromatin and can-
cer. Nat Rev Cancer 2004, 4:133–142
86. Tyler JK, Kadonaga JT: The “dark side” of chromatin remodeling:
repressive effects on transcription. Cell 1999, 99:443– 446
87. Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J,
Sanchez-Cespedes M: Frequent BRG1/SMARCA4-inactivating muta-
tions in human lung cancer cell lines. Hum Mutat 2008, 29:617– 622
88. Zhang ZK, Davies KP, Allen J, Zhu L, Pestell RG, Zagzag D, Kalpana
GV: Cell cycle arrest and repression of cyclin D1 transcription by
INI1/hSNF5. Mol Cell Biol 2002, 22:5975–5988
89. Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann
M, Crabtree GR, Goff SP: The retinoblastoma protein and BRG1
form a complex and cooperate to induce cell cycle arrest. Cell,
1994 79:119–130
90. Gibbons RJ, Higgs DR: Molecular-clinical spectrum of the ATR-X
syndrome. Am J Med Genet 2000, 97:204 –212
91. Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP,
Fryer A, Goudie DR, Krantz ID, Traeger-Synodinos J: Mutations in
the chromatin-associated protein ATRX. Hum Mutat 2008, 29:
796 802
92. Yoo CB, Jones PA: Epigenetic therapy of cancer: past, present and
future. Nat Rev Drug Discov 2006, 5:37–50
93. Johnstone RW: Histone-deacetylase inhibitors: novel drugs for the
treatment of cancer. Nat Rev Drug Discov 2002, 1:287–299
94. Marks PA, BreslowR: Dimethyl sulfoxide to vorinostat: development of
this histone deacetylase inhibitor as an anticancer drug. Nat Biotech-
nol 2007, 25:84–90
95. Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL,
Leighton JK, Patel H, Rahman A, Sridhara R, Wang YC, Pazdur R:
FDA: Approval summary—azacitidine for treatment of myelodysplas-
tic syndrome subtypes. Clin Cancer Res 2005, 11:3604–3608
96. Tefferi A, Letendre L: Drug therapy for myelodysplastic syndrome:
building evidence for action. Cancer 2006, 106:1650 –1652
97. Issa JP: DNA methylation as a therapeutic target in cancer. Clin
Cancer Res 2007, 13:1634 –1637
98. Calabro` L, Fonsatti E, Altomonte M, Pezzani L, Colizzi F, Nanni P,
Gattei V, Sigalotti L, Maio M: Methylation-regulated expression of
cancer testis antigens in primary effusion lymphoma: immunothera-
peutic implications. J Cell Physiol 2005, 202:474 477
99. Glaser KB: HDAC inhibitors: clinical update and mechanism-based
potential. Biochem Pharmacol 2007, 74:659 671
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    • "Deregulation of the epi-genome is another accepted mechanism that results in extensive changes to gene expression in cancers [104,105]. FBPs can directly and indirectly affect the epi-genome. Fbxl10 (KDM2B/JHDM1B) and Fbxl11 (KDM2A/JHDM1A) function as ubiquitin ligases but also as demethylases, which can modify histone H3 [105][106][107]. "
    [Show abstract] [Hide abstract] ABSTRACT: F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.
    Full-text · Article · Sep 2015
    • "Epigenetic mechanisms (the study of heritable changes in gene expression that occur independent of changes in the primary DNA sequence) are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals [1] . Disruption of such epigenetic processes can lead to altered gene function and malignant cellular transformation [2] . Among epigenetic changes, DNA methylation is a stable but reversible epigenetic modification that regulates gene expression [3]. "
    [Show abstract] [Hide abstract] ABSTRACT: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are essential compounds in the carbon metabolic cycle that have clinical implications in a broad range of disease conditions. The measurement of the ratio SAM/SAH also called methylation index, has become a way of monitoring the DNA methylation of a cell which is an epigenetic event with important clinical implications in diagnosis; therefore the development of suitable methods to accurately quantify these compounds is mandatory. This work illustrates the comparison of three independent methods for the determination of the methylation index, all of them based on the chromatographic separation of the two species (SAM and SAH) using either ion-pairing reversed phase or cation exchange chromatography. The species detection was conducted using either molecular absorption spectrophotometry (HPLC–UV) or mass spectrometry with electrospray (ESI-MS/MS) as ionization source or inductively coupled plasma (DF-ICP-MS) by monitoring the S-atom contained in both analytes. The analytical performance characteristics of the three methods were critically compared obtaining best features for the combination of reversed phase HPLC with ESI-MS in the MRM mode. In this case, detection limits of about 0.5 ng mL−1 for both targeted analytes permitted the application of the designed strategy to evaluate the effect of cisplatin on the changes of the methylation index among epithelial ovarian cancer cell lines sensitive (A2780) and resistant (A2780CIS) to this drug after exposition to cisplatin.
    Full-text · Article · May 2015
    • "Given the profound epigenetic divergence that prevails in tumor cells (Akhtar-Zaidi et al., 2012; De Carvalho et al., 2012), it is foreseeable that tumor-specific gene expression response profiles induced by virus infection may be altered by epigenetic modifications and that this could contribute to the heterogeneity of tumor responsiveness to OVs. As discussed previously, epigenetic reprogramming is well known to play an important role in oncogenic transformation and numerous reviews extensively cover the role of epigenetics in cancer (Muntean and Hess, 2009; Baylin and Jones, 2011; Hatziapostolou and Iliopoulos, 2011; Suva et al., 2013 ). Thus, the remainder of this review aims to highlight current knowledge of genes epigenetically regulated in cancer that are also involved in pathways critical for OV therapy, namely the IFNmediated antiviral response and antigen presentation (Table 1), and how this contributes to tumor heterogeneity (Figure 1). "
    [Show abstract] [Hide abstract] ABSTRACT: Oncolytic viruses (OVs) comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed.
    Full-text · Article · Sep 2013
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