HATs and HDACs: from structure, function and regulation to novel
strategies for therapy and prevention
X-J Yang1and E Seto2
1Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montre ´al, Que ´bec, Canada and2Molecular
Oncology Program, H Lee Moffitt Cancer Center, Tampa, FL, USA
Acetylation of the e-amino group of a lysine residue was
first discovered with histones in 1968, but the responsible
enzymes, histone acetyltransferases and deacetylases,
were not identified until the mid-1990s. In the past
decade, knowledge about this modification has exploded,
with targets rapidly expanding from histones to transcrip-
tion factors and other nuclear proteins, and then to
cytoskeleton, metabolic enzymes, and signaling regulators
in the cytoplasm. Thus, protein lysine acetylation has
emerged as a major post-translational modification to
rival phosphorylation. In this issue of Oncogene, 19
articles review various aspects of the enzymes governing
lysine acetylation, especially about their intimate links to
cancer. To introduce the articles, we highlight here four
central themes: (i) multisubunit enzymatic complexes;
(ii) non-histone substrates in diverse cellular processes;
(iii) interplay of lysine acetylation with other regulatory
mechanisms, such as noncoding RNA-mediated gene
silencing and activation; and (iv) novel therapeutic
strategies and preventive measures to combat cancer and
other human diseases.
Oncogene (2007) 26, 5310–5318; doi:10.1038/sj.onc.1210599
Keywords: lysine acetylation; histone acetylase; histone
deacetylase; signaling; tubulin
Four decades on acetyllysine: from infancy to prime years
Protein lysine acetylation refers to post-translational
addition of an acetyl moiety to the e-amino group of a
lysine residue (Figure 1). This reversible modification is
also known as Ne-acetylation and is different from
protein N-terminal acetylation (or Na-acetylation).
Acetylation of histone proteins was first discovered in
the early 1960s (Phillips, 1963; Allfrey et al., 1964), with
the chemical nature defined as Ne-acetylation a few years
later (Gershey et al., 1968). A recent citation report on
Allfrey’s initial description about the potential link of
histone modifications to gene activity shows that the
field has gone through ups and downs (Figure 2). There
was a surge of research interests during the 7–8 years
after the initial discovery of histone acetylation, but it
then cooled off and reached the lowest moment in the
early 1990s. Importantly, the research interests surged
again afterwards. Identification of the first histone
acetyltransferases (HATs) and histone deacetylases
(HDACs) in the mid-1990s directly linked histone
acetylation to gene regulation and contributed to the
sustainable surge of interests (Brownell and Allis, 1995;
Kleff et al., 1995; Bannister and Kouzarides, 1996;
Brownell et al., 1996; Mizzen et al., 1996; Ogryzko
et al., 1996; Parthun et al., 1996; Rundlett et al., 1996;
Taunton et al., 1996; Yang et al., 1996a,b). In addition,
four founding members of the MYST (monocytic
leukemia zinc finger protein (MOZ), Ybf2/Sas3, some-
thing about silencing 2 (Sas2) and HIV Tat-interactive
protein of 60kDa (TIP60)) family were cloned around
that time and proposed to possess HAT activity,
suggesting a putative link of histone acetylation
to leukemogenesis, gene silencing and HIV biology
(Borrow et al., 1996; Kamine et al., 1996; Reifsnyder
et al., 1996). As many of us have excitingly witnessed,
the field has experienced an exponential growth in the
past decade and is gradually reaching its maturity
(Figure 2) (reviewed by Jenuwein and Allis, 2001; Lin
and Dent, 2006; Goldberg et al., 2007; Kouzarides,
2007; Li et al., 2007; Shahbazian and Grunstein, 2007).
As is often the case, a hot field spreads out and affects
neighboring areas. Indeed, research of histone acetyla-
tion has had an important impact on studies of
other proteins. Over 20 years ago, acetyllysine residues
were found in HMG1 (high-mobility group protein 1)
(Sterner et al., 1979) and a-tubulin (L’Hernault and
Rosenbaum, 1985; Piperno and Fuller, 1985). A decade
ago, HATs were first reported to acetylate the tumor
suppressor p53 and two general transcription factors
(Gu and Roeder, 1997; Imhof et al., 1997), leading to the
notion that HATs and HDACs are not just for histones.
As a result, many investigators rushed to test various
transcription factors. Since then, over 60 of them have
been shown to be subjected to Ne-acetylation (for
reviews, see Kouzarides, 2000; Sterner and Berger,
2000; Cohen and Yao, 2004; Yang and Gre ´ goire, 2007).
Importantly, this has been extended to many regula-
tors of DNA repair, recombination and replication;
Correspondence: Dr X-J Yang, Molecular Oncology Group, Depart-
ment of Medicine, McGill University Health Center, RVH, Room H5.
41, 687 Pine Avenue West, Montre ´ al, Que ´ bec H3A 1A1, Canada and
Dr E Seto, Molecular Oncology Program, H Lee Moffitt Cancer
Centre, Tampa, FL, USA.
E-mail: firstname.lastname@example.org and email@example.com
Oncogene (2007) 26, 5310–5318
& 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00
viral proteins; classical metabolic enzymes, such as
bacterial and mammalian acetyl-CoA synthases; and
recently to kinases, phosphatases and other signaling
regulators (Figure 3). Moreover, three proteomic studies
identified acetyllysine residues in a diverse array of
proteins (Iwabata et al., 2005; Kim et al., 2006; Xie
et al., 2007). Due to historical reasons, we maintain the
original acronyms HATs and HDACs, but their present
meanings are quite different from what they stood for 10
These enzymes may also control lysine acetylation-
like modifications, such as propioylation and butyryla-
tion (Chen et al., 2007). Protein O-acetylation has just
been discovered and directly competes with phosphory-
lation (Mittal et al., 2006; Mukherjee et al., 2006).
The bacterial protein mediating this modification
also promotes Ne-acetylation, so it will be interesting
to investigate whether HATs and HDACs are involved in
governing O-acetylation. Thus, this special issue of Onco-
gene is not only valuable for researchers investigating
transcription and other chromatin-based nuclear pro-
cesses, but also should be of immediate interests to those
who are studying metabolism, cytoskeleton, cell division,
apoptosis and signaling.
(Lys) residue. A HAT catalyzes the transfer of an acetyl group
from acetyl CoA to the e-amino group of the lysine residue. With a
water molecule, an HDAC promotes the removal of the acetyl
group from acetyllysine (Ac-Lys), regenerating the e-amino group
and releasing an acetate molecule. Strictly speaking, it is more
appropriate to use general terms such as protein lysine acetyl-
transferase and deacetylase to refer to the enzymes for non-histone
protein substrates. Since known HATs and HDACs show activity
towards histones and other proteins, these acronyms have been
used even when non-histone substrates are in question. Also shown
are small molecules and different biological conditions that may
inhibit or stimulate HAT and HDAC activities. While HDAC
inhibitors have been actively evaluated in clinical trials, HATs have
not been seriously considered as drug targets. The bromodomain
is well known to serve as an acetyllysine-recognizing module, but
it is unclear if there are other domains with similar function.
HAT, histone acetyltransferase; HDAC, histone deacetylase;
TSA, Trichostatin A.
Cartoon illustrating reversible acetylation of a lysine
Number of Citation
Year of Citation
(1964). The paper was the first to suggest the potential link of
histone acetylation and methylation to gene activities. The chart
was based on an ISI citation report performed on the Web of
Science (http://portal.isiknowledge.com/portal.cgi) in the second
week of April 2007. It roughly records the ups and downs in the
chromatin field and nicely illustrates that sometimes the full
potential of an important discovery can only be realized decades
later. A peak of citation reflects a surge of research interests in
related topics in the same and preceding years. There could be
many factors contributing to the formation of each peak. For
example, in addition to identification of the first HATs and
HDACs, studies of chromatin structure per se and biochemical
purification of ATP-dependent remodeling molecular machines
were important for the surge of citation in the early and mid-1990s
(for reviews, see Hansen and Ausio, 1992; Adams and Workman,
1993; Turner, 1993; Becker, 1994; Paranjape et al., 1994; Wolffe,
1994; Peterson and Tamkun, 1995).
Citation chart of the landmark paper by Allfrey et al.
H3, H4, H1
c-Abl tyrosine kinase
HATs & HDACs
SV40 T antigen
DNA pol β & ε
lysine (K) acetylation in diverse cellular processes. The hexagon
with the letter A refers to acetylation. For each process, only
representative proteins are listed. In particular, acetylation of
acetyl-CoA synthase is a key regulatory mechanism conserved from
bacteria to humans (Starai et al., 2002; Hallows et al., 2006; Schwer
et al., 2006). Cdk9, cyclin-dependent kinase 9; FEN1, Flap
endonuclease 1; NBS1, Nijmegen breakage syndrome protein 1;
PCNA, proliferating cell nuclear antigen; PTEN, phosphatase and
tensin homolog; Rb, retinoblastoma suppressor protein.
Schematic illustration of the prevalence of reversible
Histone acetyltransferases and deacetylases
X-J Yang and E Seto
HATs of different types and sizes
There are three major families of HATs: general control
non-derepressible 5 (Gcn5)-related N-acetyltransferases
(GNATs), p300/CBP and MYST proteins (reviewed by
Sterner and Berger, 2000; Roth et al., 2001; Lee and
Workman, 2007). p300 (adenoviral E1A-associated
protein of 300kDa) and CBP (CREB-binding protein)
form a pair of paralogous transcriptional coacti-
vators and have been extensively reviewed elsewhere
(Goodman and Smolik, 2000), so only the GNAT and
MYST families are covered in this issue. Members of the
GNAT family include HAT1 (histone acetyltransferase
1), yeast Gcn5 and its metazoan orthologs GCN5 and
PCAF (p300/CBP-associated factor). In this issue, four
articles are devoted to the discussion of these HATs.
Parthun (2007) summarizes the discovery and studies of
HAT1, which is conserved from yeast to man and has a
key role in chromatin assembly. Baker and Grant (2007)
describe the latest developments about the Gcn5-
containing multisubunit complex SAGA (Spt-Ada-
(2007) focus on GCN5/PCAF complexes from Droso-
phila and mammals. Then, Murr et al. (2007) review
studies of TRRAP (transformation/transcription do-
main–associated protein), which was initially identified
as a c-Myc-binding transcriptional coactivator and
subsequently shown to be an integral subunit of a
PCAF complex (McMahon et al., 1998; Vassilev et al.,
1998). Related to this, yeast Tra1 (TRRAP-related
protein 1) is a subunit of SAGA (Grant et al., 1998;
Saleh et al., 1998). Moreover, Tra1 and TRRAP are
subunits of yeast Esa1 (essential Sas2-related acetyl-
transferase 1) and human TIP60 complexes, respectively
(Allard et al., 1999; Ikura et al., 2000). Esa1 and TIP60
are orthologous and belong to the MYST family
(Doyon and Cote, 2004). Compared to Gcn5/PCAF
and p300/CBP, this family is less well known, so it is
extensively covered in this edition, Lafon et al. (2007) on
Esa1, Sas2 and Sas3, the three MYST proteins from
lian orthologs of Mof (male absent on the first), a key
regulator of Drosophila gene dosage compensation;
Avvakumov and Co ˆ te ´ (2007) outlining the characteriza-
tion of mammalian MYST proteins; and Yang and
Ullah (2007) detailing studies of MOZ and MORF
(MOZ-related factor), a pair of paralogs with direct
links to leukemia and highly conserved from zebrafish to
In addition to those mentioned above, over 10 other
proteins have been reported to possess HAT activity
(for reviews, see Sterner and Berger, 2000; Roth et al.,
2001; Yang, 2004; Lee and Workman, 2007). Among
them are Elp3 (Elongator protein 3), Eco1 (establish-
ment of cohesion 1) and CDY (chromodomain on Y
chromosome), which exhibit sequence similarity to
members of the GNAT family. Functional significance
of the HAT activities reported for several transcription
factors, including TAFII250, SRC1 (steroid receptor
coactivator 1) and one of its paralogs, ATF2, TFIIB and
CLOCK, remains to be substantiated further. Different
laboratories have recently reported that yeast Rtt109
acetylates lysine 56 of yeast histone H3 (Ivanov et al.,
2002; Collins et al., 2007; Driscoll et al., 2007; Han et al.,
2007; Tsubota et al., 2007; Xhemalce et al., 2007). It shows
no obvious sequence similarity to other known HATs, so
it represents a novel family. Although there are no
apparently related proteins in mammals, this important
discovery suggests that additional HATs may remain to be
identified. Consistent with this suggestion, acetyllysine
residues are present in various proteins (Figure 3).
The classical and sirtuin families of HDACs
Dependent on sequence similarity and cofactor depen-
dency, HDACs are grouped into four classes and two
families: the classical and silent information regulator 2
(Sir2)-related protein (sirtuin) families. In humans,
members of the classical family include HDAC1, -2, -3
and -8 (class I); HDAC4, -5, -6, -7, -9 and -10 (class II);
and HDAC11 (class IV) (reviewed by Cress and Seto,
2000; Grozinger and Schreiber, 2002; Blander and
Guarente, 2004; Gregoretti et al., 2004). They share
sequence similarity and require Zn2þfor deacetylase
activity. The sirtuin family contains seven members
(SIRT1–7, class III), which show no sequence resem-
blance to members of the classical family and require
NADþas the cofactor. In this issue of Oncogene,
the second set of eight articles is devoted to HDACs.
Glozak and Seto (2007) summarize various links of
these enzymes to cancer. Denslow and Wade (2007)
present an overview of different HDAC1/2 complexes
along with a detailed discussion on NuRD (nucleosome
remodeling deacetylase complex), an HDAC1/2 com-
plex with intimate links to cancer metastasis. Karagianni
and Wong (2007) cover different aspects of HDAC3
complexes, including their links to histone demethyla-
tion and cell-cycle regulation. Aufsatz et al. (2007)
illustrate how Hda6 (histone deacetylase 6), a class I
HDAC from the model plant Arabidopsis, may interplay
with different chromatin modifiers and direct hetero-
chromatin formation. Martin et al. (2007) review recent
developments about the function and regulation of
HDAC4, -5, -7 and -9 (forming a subgroup known as
class IIa) and Boyault et al. summarize studies of
HDAC6 and HDAC10 (class IIb). While Saunders and
Verdin (2007) present an overview of mammalian
sirtuins, Vaquero et al. (2007) focus on multiprotein
complexes of three sirtuins and emphasize their links to
histone H4 hypoacetylation at lysine 16, an epigenetic
hallmark in cancer cells.
Structural basis for acetylation recognition and
Following the above two sets of articles on the complex
composition, function and regulation of HATs and
HDACs are two papers about the three-dimensional
structures. Mujtaba et al. summarize structural studies
Histone acetyltransferases and deacetylases
X-J Yang and E Seto
of the bromodomain, a protein module that can
recognize acetyl-lysine motifs and is often found in
HATs and other chromatin regulators. Hodawadekar
and Marmorstein (2007) outline crystal structures of
HATs and HDACs, describe the catalytic mechanisms
involved and discuss how the information can be used to
design small molecule effectors targeting these enzymes
for treatment of related diseases like cancer. In the last
article of this issue, Xu et al. (2007) review classical
HDAC inhibitors as therapeutic agents and the mole-
cular mechanisms of action.
HAT and HDAC complexity: stay alone or with others?
One important theme about these enzymes is that they
often exist in multiprotein complexes stable enough to
be purified through biochemical fractionation. For
example, yeast Gcn5 is a catalytic subunit of four stable
complexes (Lee and Workman, 2007; Baker and Grant,
2007; Nagy and Tora, 2007), and HDAC3 is the
catalytic subunit of different complexes (Li et al.,
2006; Karagianni and Wong, 2007). Within these
complexes, non-catalytic subunits tend to regulate the
specific activity and substrate specificity of catalytic
subunits. For polymer substrates, the action needs to be
region-specific. For example, chromatin is polymeric
and region-specific action is crucial. This is also true
for cytoskeleton structures like microtubules. Unlike
protein kinases, there are no obvious consensus motifs
at acetylation sites for a given acetyltransferase, so
physical proximity is key for substrate recognition and
Many studies with non-histone substrates or small-
molecule effectors (for example, HDAC inhibitors) have
been carried out with recombinant proteins, so an
interesting question is whether the catalytic subunits (for
example, Gcn5 and HDAC3) are all in complex forms
associated with other subunits in vivo. Related to this,
HDAC1 and HDAC2 are found together in many
multiprotein complexes (Zhang et al., 1998; Grozinger
and Schreiber, 2002; Denslow and Wade, 2007; Nicolas
et al., 2007; Tahiliani et al., 2007), so an important issue
is whether these two deacetylases always stay and
function together. Recent studies of human and mouse
HDAC2 (Zhu et al., 2004; Ropero et al., 2006; Trivedi
et al., 2007) suggest that it can function independently
from HDAC1 in vivo, so depending on cellular contexts,
complex formation may just represent one particular
Collaborative spirit of HATs and HDACs
Only lysine acetylation and the responsible enzymes are
covered in this special issue, but it does not mean that
this is the sole regulatory mechanism nor does it imply
that such a mechanism acts alone in vivo. To understand
the structure, function and regulation of HATs and
HDACs, it is very important to consider them in a
cellular context-dependent manner, especially how they
interplay with other regulators. The interplay occurs in
at least six different mechanisms (Figure 4). First, in
addition to acetylation, the e-amino group of a lysine
residue is subject to other modifications, including
methylation, ubiquitination, sumoylation, propioylation
and butyrylation. Acetylation would preclude other
modifications, and vice versa. Thus, HATs and HDACs
control the availability of a lysine residue for other
covalent modifications (Figure 4a). Such a mechanism
has been well documented for lysine 9 of histone H3 in
fission yeast, where deacetylation primes it for methyl-
(Yamada et al., 2005). Plant Hda6 plays a key role in
organizing heterochromatin (Earley et al., 2006; Aufsatz
et al., 2007). There is also evidence that hypoacetylation
is a prerequisite for heterochromatin formation and
gene silencing in mammals (Zaratiegui et al., 2007).
Furthermore, acetylation has been shown to preclude
ubiquitination of Smad7 and sumoylation of p300,
MEF2, and others (reviewed by Yang and Gre ´ goire,
Second, acetylation of a lysine residue might affect
modification of a neighboring residue. As shown in
Figure 4b, lysine acetylation affects phosphorylation of
an adjacent serine residue, which has been shown for
other modifications (a and b) and models on putative roles of
ncRNA in targeting HATs and HDACs to specific chromatin loci
(c and d). (a) Acetylation of a lysine (K) residue precludes its
methylation, ubiquitination, sumoylation or other lysine modifica-
tions. The hexagon with the letter A refers to acetylation, and an
oval with the letter M is for methylation. (b) Acetylation of a lysine
(K) residue hinders phosphorylation of an adjacent serine(s)
residue. An oval with the letter P is for phosphorylation. (c)
ncRNA recruits an HAT complex, such as rox RNA in the
Drosophila Mof complex, to carry out region-specific acetylation.
(d) ncRNA recruits an HDAC, such as Hda6 by micro RNA in
Arabidopsis, to achieve gene- or chromatin domain-specific
deacetylation. Gray oval, nucleosome; Ac, acetylation; ncRNA,
Cartoons showing potential interplay of acetylation with
Histone acetyltransferases and deacetylases
X-J Yang and E Seto
lysine 9 and serine 10 of histone H3, as well as for serine
10 and lysine 11 of histone H2B (Ahn et al., 2006;
Li et al., 2006).
Third, HATs and HDACs are physically linked to
other catalytic activities. Related to this, PCAF and
p300 possess intrinsic E3 and E4 ubiquitin ligase
activities, respectively (Grossman et al., 2003; Linares
et al., 2007). Moreover, an O-linked N-acetylglucosa-
mine (O-GlcNAc) transferase contains a HAT domain
(Toleman et al., 2004), whereas a putative demethylase
domain is present in Elp3 (Chinenov, 2002). Ubiquitin
protease 8 associates with Gcn5 in SAGA (Baker and
Grant, this issue). LSD1 ( lysine-specific demethylase 1)
and HDAC1/2 are present in a multiprotein complex
(Humphrey et al., 2001; Shi et al., 2004; Lee et al., 2005),
while HDAC3 associates with a Jumonji demethylase
(Karagianni and Wong, 2007). HDAC3 also interplays
with Aurora kinase B to achieve coordinated deacetyla-
tion and phosphorylation of histone H3 (Li et al., 2006).
Reminiscent of this, HDACs form complexes with
phosphatases (Canettieri et al., 2003; Brush et al.,
2004; Zhang et al., 2005).
Fourth, HATs and HDACs physically associate with
modification-specific modules for sequential actions
with different modifications. Many HATs contain
bromodomains for acetyl-lysine recognition (Mujtaba
et al., 2007). HDAC6 possesses a zinc-finger domain for
ubiquitin binding, allowing the recognition and trans-
port of ubiquitylated proteins and controlling polyubi-
quitin-chain turnover (Boyault et al., 2007). The
deacetylase and ubiquitin-binding activities of HDAC6
are required for management of misfolded proteins
(Kawaguchi et al., 2003; Iwata et al., 2005). In addition,
chromodomains, plant homeodomain-linked (PHD)
fingers and other modification-specific modules are
present in HAT and HDAC complexes (reviewed in
Seet et al., 2006; Kouzarides, 2007; Lee and Workman,
Fifth, some HATs physically associate with noncod-
ing (nc) RNA. It is well known that transcription factors
recruit HATs and HDACs to achieve sequence-specific
actions. Similar to transcription factors, ncRNA may
target HATs and HDACs to specific chromatin regions
(Figures 4c and d). For gene–dosage compensation in
male flies, rox RNA associates with Mof and achieves
chromosome-specific acetylation of histone H4 at lysine
16 (Lucchesi et al., 2005; Rea et al., 2007; Straub and
Becker, 2007). Related to this, SRA (steroid receptor
RNA activator) functions as a transcriptional coactiva-
tor and may interact with HATs (Lanz et al., 1999).
MicroRNA may be involved in targeting plant Hda6 for
histone deacetylation (Aufsatz et al., 2007). The ques-
tion whether HDACs play a role in other ncRNA-
mediated silencing phenomena, such as X-chromosome
inactivation, will be an important issue to address in the
future (Zaratiegui et al., 2007).
Sixth and finally, different HATs may target one
substrate. For example, p300, PCAF and two members
of the MYST family acetylate p53 (Gu and Roeder,
1997; Sakaguchi et al., 1998; Liu et al., 1999; Sykes
et al., 2006; Tang et al., 2006). Similarly, different
HDACs bind to a single target (Gre ´ goire et al., 2007 and
references therein). Related to this, pan-HDAC inhibi-
tors may be more effective (Xu et al., 2007), a concept
that is similar to the combinatory principle to be
Novel therapeutic strategies: from butyrate to Vorinostat
Butyrate was discovered to be an HDAC inhibitor 30
years ago (Riggs et al., 1977; Candido et al., 1978; Sealy
and Chalkley, 1978). It exerts various biological effects
on cultured cells, including growth suppression, cell-
cycle arrest and induction of cell differentiation,
suggesting a potential link between histone deacetyl-
ation and cell-static effects. Butyrate has other bio-
chemical activities, so it is not a specific inhibitor. About
12 years later, the fungi-static antibiotic Trichostatin A
was identified as the first specific inhibitor and found
to induce cell differentiation (Yoshida et al., 1990),
strengthening the link between histone deacetylation
and cell-static effects. HDAC inhibition has become a
promising strategy for therapeutic intervention. For
example, suberoylanilide hydroxamic acid (SAHA, now
marketed as Vorinostat) was identified as an HDAC
inhibitor B10 years ago (Richon et al., 1998) and was
recently approved for treatment of cutaneous T-cell
lymphoma (Xu et al., 2007). Many pharmaceutical
companies have active programs on related inhibitors
that target the classical family of HDACs (for recent
reviews, see Minucci and Pelicci, 2006; Marchion and
Munster, 2007; Rasheed et al., 2007). Paradoxically,
activators of sirtuins are promising agents against
cancer and aging (Saunders and Verdin, 2007). Such
activators are being evaluated by at least two pharma-
ceutical companies. By contrast, HATs have not been
seriously considered as drug targets by the pharmaceu-
tical industry. In theory, modulation of HAT activity
should also be effective (Figure 1).
As discussed above, HATs and HDACs interplay
with other regulators (Figures 4a and b), so it is
tempting to speculate that more effective results can be
achieved if modulation of lysine acetylation is combined
with other therapeutic approaches, such as inhibition of
DNA methylation, activation of nuclear receptors,
kinase inhibition and RNA interference. Thus, this
edition of Oncogene may also be useful for newcomers
in the field to seek combinatory effects of different
Novel preventive measures: from healthy foods to
HATs and HDACs are also important for generating
valuable information on disease prevention. Short-chain
fatty acids such as butyrate, produced by microbial
fermentation of dietary fiber in the large intestine, inhi-
bit classical HDACs. Elevated expression of HDAC2
was suggested to be a causal factor for colon and gastric
cancers (Zhu et al., 2004), so dietary inhibition may have
Histone acetyltransferases and deacetylases
X-J Yang and E Seto
preventive value, which is perhaps one contributing
factor to low prevalence of colon cancer in Asia.
Inhibitors of classical HDACs, diallyl disulfide and
sulforaphane are present in garlic and broccoli, respec-
tively (Druesne et al., 2004; Myzak et al., 2004).
Resveratrol (a sirtuin activator) and related polyphenols
are found in nuts, certain plant leaves, dark cherries and
the skin of red grapes (thus red wine). Moreover,
curcumin (the principal curcuminoid of an Indian curry
spice) and two other natural products inhibit HAT
activity (Balasubramanyam et al., 2004).
Like sirtuins, class I/II HDACs are subject to
regulation by various physiological and pathological
stimuli (Figure 1). Some evidence suggests that at least
in mouse models, function of class IIa HDAC is
regulated by neuronal stimuli (Mejat et al., 2005;
Belfield et al., 2006), immune activity (Dequiedt et al.,
2003), physical exercise (Berdeaux et al., 2007) and
perhaps fasting (Koo et al., 2005; Berdeaux et al., 2007).
Adverse conditions such as smoking were reported
to alter the expression of class I/II HDACs in smokers
(Ito et al., 2005). Moreover, a high-salt diet was found
to induce the expression of a kinase that can block the
functioning of class IIa HDACs in rats (Okamoto et al.,
2004; Berdeaux et al., 2007; van der Linden et al., 2007).
In sum, as we have witnessed in the past decade, studies
of HATs and HDACs will continue to yield important
knowledge not only on therapy and for intellectual
curiosity, but also for determining how to prevent
effectively cancer and other diseases.
We are grateful to Dr Prem Reddy for vision and support, the
contributors for enthusiasm and B40 anonymous referees for
critical evaluation of the articles. We apologize to those whose
works are unintentionally omitted in this issue because of
knowledge and space limitation. Our research has been
supported by grants from the NIH (to ES) and the Canadian
funding agencies NCIC, CIHR, CFI and NSERC (to XJY).
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