Download Epigenetic mechanisms in hepatocellular carcinoma: How

Mutation Research 727 (2011) 55–61
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Mini-review
Epigenetic mechanisms in hepatocellular carcinoma: How environmental
factors influence the epigenome
Zdenko Herceg a,*, Anupam Paliwal a,b,**
a
b
Epigenetics Group, International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France
Institute for Cancer Genetics, Columbia University Medical Center 1130 St. Nicholas Avenue, New York, NY 10032, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 5 January 2011
Received in revised form 5 April 2011
Accepted 6 April 2011
Available online 15 April 2011
Epigenetic mechanisms maintain heritable changes in gene expression and chromatin organization over
many cell generations. Importantly, deregulated epigenetic mechanisms play a key role in a wide range
of human malignancies, including liver cancer. Hepatocellular carcinoma (HCC), which originates from
the hepatocytes, is by far the most common liver cancer, with rates and aetiology that show considerable
geographic variation. Various environmental agents and lifestyles known to be risk factors for HCC (such
as infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), chronic alcohol intake, and aflatoxins)
are suspected to promote its development by eliciting epigenetic changes, however the precise gene
targets and underlying mechanisms have not been elucidated. Many recent studies have exploited
conceptual and technological advances in epigenetics and epigenomics to investigate the role of
epigenetic events induced by environmental factors in HCC tumors and non-tumor precancerous
(cirrhotic) lesions. These studies have identified a large number of genes and pathways that are targeted
by epigenetic deregulation (changes in DNA methylation, histone modifications and RNA-mediated gene
silencing) during the development and progression of HCC. Frequent identification of aberrant
epigenetic changes in specific genes in cirrhotic tissue is consistent with the notion that epigenetic
deregulation of selected genes in pre-malignant lesions precedes and promotes the development of HCC.
In addition, several lines of evidence argue that some environmental factors (such as HBV virus) may
abrogate cellular defense systems, induce silencing of host genes and promote HCC development via an
‘‘epigenetic strategy’’. Finally, profiling studies reveal that HCC tumors and pre-cancerous lesions may
exhibit epigenetic signatures associated with specific risk factors and tumor progression stage. Together,
recent evidence underscores the importance of aberrant epigenetic events induced by environmental
factors in liver cancer and highlights potential targets for biomarker discovery and future preventive and
therapeutic strategies.
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Epigenetics
Cancer risk-factor
Environment
DNA methylation
Histone modifications
Noncoding RNAs
Liver cancer
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HCC and aberrant DNA methylation changes . . . . . . . .
Aberrant histone modification changes in HCC . . . . . .
Noncoding RNAs (micro and long noncoding RNAs) in
Epigenetics-based therapy for HCC . . . . . . . . . . . . . . . .
Conclusions and future directions. . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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HCC
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1. Introduction
* Corresponding author. Tel.: +33 4 72 73 83 98; fax: +33 4 72 73 83 29.
** Corresponding author.
E-mail addresses: [email protected] (Z. Herceg), [email protected] (A. Paliwal).
1383-5742/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.mrrev.2011.04.001
Hepatocellular carcinoma (HCC) is a well-recognized complication of cirrhosis. Infection by hepatitis B (HBV) and hepatitis C
HCV viruses, chronic alcoholism, aflatoxin exposure, smoking and
[()TD$FIG]
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Z. Herceg, A. Paliwal / Mutation Research 727 (2011) 55–61
Fig. 1. Genetic and epigenetic events in the onset and progression of hepatocellular carcinoma. Infections with hepatitis B and C viruses, alcoholism, exposure to aflatoxin,
hypertension and diabetes are the major HCC associated risk factors. Through different mechanism(s) exposure to various risk factors induces hepatocellular injuries,
inflammatory responses and cirrhosis. Inflammatory and immune responses are accompanied by cytokine production, generation of reactive oxygen species, increased DNA
damage rates and high metabolic rates, all of which increase the possibility of disruption of both genetic and epigenetic events in hepatocytes. In cirrhotic liver tissue
hepatocytes susceptibility to neoplastic transformation is further influenced by their epigenetic and genetic state. The onset and progression of HCC is often caused by mutual
and synergistic interactions between several abnormal epigenetic and genetic events.
possibly obesity and diabetes are believed to be the major risk
factors associated with the incidence of HCC (Fig. 1). Regardless of
aetiology the risk of malignancy is determined by the underlying
cause of liver damage, which is further influenced by age, gender
and ethnic differences in environmental and lifestyle factors [1–3].
Both genetic and epigenetic factors form the molecular basis of
HCC. Although sequences of HBV are found integrated in the
genome of HCC cells and virus-related insertional mutagenesis
occurs frequently in liver cancers, there is no consensus pattern of
viral integration [4,5]. A frequent loss of heterozygosity (LOH) in
chromosome 8p in HCC cases suggests that inactivation of the
Deleted in Liver Cancer 1 gene (DLC-1) may play a pivotal role in
HCC development [2]. In late stages of HCC development, somatic
mutations in several tumor suppressor genes (such as TP53, p16,
and RB), oncogenes (including c-MYC and b-catenin) and other
cancer-associated genes (including E-cadherin and cyclin D1) have
also been observed [2,6]. However, the significance and sequence
of these genetic events remain to be established. While germline
mutations are reflected in the familial cancer history, a risk factorassociated somatic mutation should be noticeable in most of the
cases exhibiting HCC associated with a particular risk factor. In
either case, such genetic events would have been quite evident and
with relatively rapid consequences. Contrary to this, the onset and
development of HCC is a lengthy (several years) process with
distinct stages of progression. The large time gap between initial
exposure to the risk factor(s) and HCC onset indicates that
consistent risk factor exposure, cirrhosis and lifestyle and
environmental cues may result in establishing an aberrant
epigenetic stage for HCC onset (Fig. 1).
The term ‘‘epigenetics’’ refers to all stable changes of
phenotypic traits that are not coded in the DNA sequence itself
[7–10]. Epigenetic mechanisms can be viewed as an interface
between the genome and risk factor/life style/environmental
influence. Aberrant epigenetic events associated with any of these
stressors likely play an important role in the onset and progression
of different human malignancies. The field of epigenetics has been
receiving remarkable attention recently, owing to our increased
awareness that epigenetic inheritance is essential for the
development of critical cellular processes such as gene transcription, differentiation and protection against viral genomes. Aberrant epigenetic states may predispose to genetic changes, but
genetic changes may also initiate aberrant epigenetic events.
Epigenetic and genetic mechanisms may thus work together to
silence key cellular genes and destabilize the genome, leading to
oncogenic transformation and observed the complexity and
heterogeneity in human cancers, including HCC [2,3,8].
2. HCC and aberrant DNA methylation changes
DNA methylation is a major epigenetic mechanism of gene
regulation occurring in eukaryote DNA at CpG sites, usually
enriched in the promoters of genes. In a wide range of tumors,
including HCC, global hypomethylation and specific promoter
hypermethylation have been linked with genomic instability and
inactivation of tumor suppressor genes (TSG), respectively [7–
9,11,12].
Aberrant DNA methylation changes have been reported to be
specific to the cancerous tissue making it possible to distinguish
HCC and non-HCC surrounding liver tissues. Abnormal DNA
methylation of RASSF1A, p16, CRABP1, GSTP1, CHRNA3, DOK1,
SFRP1, GAAD45a and p15 tumor suppressor genes is associated
with HCC, while hypermethylation of the CHFR (checkpoint with
forkhead associated and ring finger) and SYK (spleen tyrosine
kinase) is detected specifically in advanced stages of HCC. It is well
established that DNA methylation changes unlike genetic events,
occur in a gradual manner. Methylation of multiple CpG sites in a
CpG island located in the promoter region of a gene leads to the
complete silencing of gene-expression e.g. multiple methylations
are required for silencing of tumor suppressor genes (p16, RASSF1,
etc.) [7–9,13]. This further underlines the specificity of HCC
associated epigenetic events and helps clarify the large time gap
between the initial risk factor exposure and HCC onset. Moreover,
Z. Herceg, A. Paliwal / Mutation Research 727 (2011) 55–61
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Table 1
Major risk factors for HCC and associated epigenetic events.
HCC risk factor
Reported epigenetic event
Contribution in HCC development
Reference
HBV infection
DNA methylation
Alterations of RB1, p53 and Wnt pathways due to silencing of important
tumor suppressor genes (p16, p21, E-cadherin and GSTP1)
Altered expression of critical cellular genes (hTERT, IGFBP-3
interleukin-4 receptor and metallothionein-1F and CDH6)
miR-152, miR-602 and miR-143 MIR regulate important cellular genes
including DNMT1, RASSF1A and FNDC3B affecting pathways related to
cell death, DNA damage, recombination, and signal transduction.
Hypermethylation of Gadd45beta expression (aberrant cell cycle arrest
and diminished DNA excision repair). Hypomethylation of STAT1
(interfering with interferon-alpha signaling).
Increased histone deacetylation activity regulates iron metabolism
through affecting hepcidin expression. Overexpression of Protein
Phosphatase 2A (PP2Ac), affecting the H4 acetylation and methylation
and histone H2AX phosphorylation.
miR-122 regulates HCV replication. miR-196 regulates HMOX1/Bach1
and HCV expression.
Hypermethylation of MGMT affects the DNA repair efficiency.
CYP2E1 down regulation results in decreased mitochondrial oxidative
stress and apoptotic potential. Adh, GST-yc2 are upregulated, while
Lsdh, cytP4502c11 are downregulated
p16 silencing and hypomethylation mediated overexpression of SNGC
miR-122s expression and function is affected (skewed IGF-1R
regulatory circuitry)
[13–17]
Histone modifications
RNA interference
HCV infection
DNA methylation
Histone modifications
RNA interference
Alcoholism
DNA methylation
Histone modifications
Aflatoxin exposure
DNA methylation
RNA interference
HCC tumors exhibit specific DNA methylation signatures associated with major risk factors and tumor progression stage,
highlighting potential clinical applications of these epigenetic
changes in the diagnosis and prognosis of HCC [13–17] (Table 1).
Interestingly, distinct methylation of several independent panels
of gene promoters has also been strongly correlated with survival
after cancer therapy. The exact molecular mechanism governing
the risk factor-specific hypermethylation signature (epigenotype)
is unclear and remains an area of much current research interest
[13,18].
To better explain how a given risk factor may affect the
hepatocyte epigenome, leading to the neoplastic transformation,
we take the example of infection with HBV a well-known and
[()TD$FIG]
[23–26]
[15,27–30]
[22,31]
[9,21,32,33]
[34,35]
[13]
[36,37]
[38,39]
[40]
widely studied HCC risk factor. The presence of HBV in host
hepatocytes may result in both genetic (insertional mutation) and
epigenetic events (Fig. 2). In HBV infection-associated HCC’s, HBV
encoded protein X (HBx) was found to upregulate expression of the
DNA-methyltransferase (DNMT) genes through its transcriptional
transactivation property, thus the corresponding down-regulation
of several important cellular genes has been attributed to the
DNMT-mediated methylation of the target genes [6,13–20]. HBx
may also directly interact with DNMT’s, directing their recruitment
at specific genes and thus affecting their methylation and
expression. Methylation of some TSGs, such as the SOCS-1,
GADD45b, STAT1, APC, and p15 genes, is reportedly observed at a
higher prevalence in HCV-positive than in HCV-negative HCC
Fig. 2. A hypothetical model depicting potential genetic and epigenetic changes induced by HBV infection and integration of the viral genome that may promote
hepatocarcinogenesis. (1) HBV genome tends to integrate within the host cell-genome, which may result in insertional mutations of critical cellular genes. However no
consistent pattern of insertional mutation has been noticed among different HCC patients HCC liver samples [2,5,53]. (2) HBV encoded protein X (HBx) directly interacts with
different cellular nuclear proteins and affects cellular processes (such as DNA damage repair) resulting in high mutational rates due to a compromised DNA damage repair
capacity and integrity of cellular genome [54,55]. (3 and 4) It is hypothesized that being the DNA of a foreign pathogen, the HBV genome may be targeted for methylationmediated silencing by host surveillance machinery and the gradual spread of DNA hypermethylation may affect nearby genes or enhancers. Alternatively, activation of the
host surveillance mechanism may exhibit long-range effects resulting in hypo-/hyper-methylation of other parts of the host genome. (5–7) HBV genome exists as a
minichromosome in the host cell and uses host cellular machinery for its transcription and replication, which is further regulated epigenetically by histone modifications and
DNA methylation [19,44,48,56]. HBX may interact with and affect histone modification enzymes [24,26,47,57]. Hijacking/interfering with the host cellular transcriptional/
epigenetic machinery may result in an aberrant epigenetic state of the host cell genome making it susceptible to neoplastic transformation.
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Z. Herceg, A. Paliwal / Mutation Research 727 (2011) 55–61
tumors [3,4,21,22]. However, HCV itself, which is known as an RNA
virus, does not integrate into and directly disturb the host genome.
Interestingly, HCC epigenotype also depends on the age and gender
of the patient and has more in common with the HBV and HCV
virus-associated HCC, compared to that observed in alcohol,
aflatoxin or other lifestyle-associated HCC.
In addition to altering promoter specific methylation patterns,
HCC onset and progression is also associated with genomic
instability accompanied by the activation of oncogenes or
transposons, which in turn may promote tumorigenesis by altering
methylation states of repetitive sequences. Cancer cell genomes
undergo global hypomethylation, with malignant cells having 20–
60% less genomic 5-methylcytosine than their normal counterparts [41]. This loss is accomplished mainly by hypomethylation of
the repetitive DNA sequences that account for 20–30% of the
human genome [41]. The methylation level of LINE1 repetitive
element and satellite 2 (SAT2) in pericentromeric satellite regions
decreases along with the progression of chronic hepatitis and HCC
[6,7,11,38,39,42]. Expression of DNMT3b4, which may lack DNA
methyltransferase activity and compete with DNMT3b3 in
targeting pericentromeric satellite regions results in DNA hypomethylation on SAT2 and plays a critical role in inducing
chromosomal instability [43].
DNA methylation is also used as a common cellular defense
mechanism to silence invading foreign DNA and viral genomes.
Several recent studies have investigated whether HBV DNA is
targeted for methylation in the infected hepatocytes (Fig. 2).
Moreover, as the double-stranded DNA genome of HBV contains
distinct CpG islands in the promoter and enhancer regulatory
region for the viral genes, it has been argued that hypermethylation may silence the HBV surface antigen gene resulting in occult
HBV cases, wherein patients with HCC test negative for hepatitis B
surface antigen (HBsAg) although their liver remains infected with
HBV [4,24,44]. Investigations have revealed that the HBV genome
is hypermethylated in both premalignant (cirrhosis) and malignant (HCC) tissues, compared with nontumor liver tissues,
suggesting that hypermethylation of the viral genome must also
be strongly associated with the malignant process. However,
patterns of HBV genome methylation in cirrhotic and tumor tissues
from both occult and non-occult HBV-infected samples reportedly
remain similar. This indicates that hypermethylation of the HBV
genome resulting from deregulated DNA methylation in malignant
cells may contribute to the disease phenotype, but is unlikely to be
responsible for the occult status. Therefore, the exact biological
significance of the observed methylation in HBV genome and its
role in HCC remains unclear [4,44].
3. Aberrant histone modification changes in HCC
Recent studies have revealed the importance of histonemodifying enzymes and ATP-dependent chromatin remodeling
complexes in regulating access to DNA for various transcription
factors and DNA repair proteins necessary for catalyzing the
critical chromatin activities of transcription, replication or DNA
repair. Histone (chromatin) modifications comprise covalent posttranslational modifications of histone proteins. The N-terminal
tails of nucleosomal histones are subject to different modifications,
including acetylation, methylation, phosphorylation and ubiquitination, which appear to work together with other epigenetic
mechanisms in establishing and maintaining gene activity states,
thus regulating a wide range of cellular processes. Different histone
modifications themselves act in a coordinated and orderly fashion
to regulate cellular processes such as gene transcription, DNA
replication and DNA repair. Alterations in the function of histonemodifying molecules and protein complexes disrupt the pattern
and levels of histone marks and consequently deregulate the
control of chromatin-based processes, which ultimately leads to
oncogenic transformation and development of cancer [8,9,12,45].
HCC has been reported to display altered histone modification
machinery and as a result an altered cellular epigenetic state. Most
of the known HCC-associated aberrant histone modification events
affect expression of critical cellular genes and thus impair normal
cellular activities (Table 1). Several such modifications are
associated with the onset of HCC and act as a susceptibility factor
for HCC, e.g. Patt1 (a GNAT family acetyltransferase) is highly
expressed in a normal healthy liver and is downregulated in HCC.
Low levels of this acetyltransferase result in a hypoacetylated
(inactive) state of apoptotic genes, affecting the apoptotic potential
of cancerous hepatocytes [23–26]. Similarly, dimethylation of
histone H3 at lysine 4 (H3K4diMe) is expressed at almost
undetectable levels in HCC. These low levels of the H3K4diMe
histone mark, were found to be caused by compromised expression
of H3K4 methylating (Ash2 complex) and demethylating enzymes
(LSD1) [46].
Certain histone code alterations are a signature for specific risk
factor exposures e.g. HCV infection induces an overexpression of
Protein Phosphatase 2A (PP2Ac), which binds to protein arginine
methyltransferase 1 (PRMT1) and inhibits its activity. PRMT1
catalyzes the methylation of histone H4 on arginine 3 and also
plays an important role in DNA repair by dephosphorylating the
damage-induced phosphorylation of H2AX (g-H2AX). Hence,
PP2Ac overexpression in HCV-associated HCCs leads to compromised histone H4 methylation/acetylation and histone H2AX
phosphorylation, significantly changing the expression of genes
important for hepatocarcinogenesis and inhibiting DNA damage
repair. In fact, overexpression of this important phosphatase is
considered a critical early event in hepatocarcinogenesis in the
context of chronic viral hepatitis [9,21,32]. In alcohol-associated
HCCs it is suggested that deregulated histone modification downregulates CYP2E1 expression, resulting in decreased mitochondrial
oxidative stress and apoptotic potential [36,37]. HBV-encoded HBx
protein is considered an oncogenic transcription factor and has
been proven to affect the expression of important cellular genes
due to its transcription transactivation and transrepression
properties. HBx has been reported to induce cellular transformation by affecting the expression of numerous genes involved in the
control of the cell cycle or apoptosis. The transcription transactivation property of HBx is supported by the fact that HBx directly
interacts with histone acetyltransferase complex CBP/P300. HBxmediated recruitment of CBP/P300 complex promotes transactivation activity, resulting in an acetylated (active) histone state of the
target cellular genes [23–26,47]. Interestingly, as the HBV genome
remains in a minichromosomal structure (bound with histone and
non-histone proteins) in the infected hepatocytes, HBx also
regulates replication and transcription of both the viral genome
and genes by influencing the epigenetic (acetylation) state of the
histone molecules in the viral minichromosomes [4,19,48]. A
recent study, perhaps surprisingly, revealed a histone deacetylase
(HDAC) as a direct HBx-interacting partner, explaining its
transrepressive activities [26]. However, it also raises the question
of whether HBx associates with other members of the cellular
epigenetic machinery and what governs these interactions (Fig. 2).
The time gap observed between the infection with HBV and the
actual onset of HCC indicates that interaction between HBx and
epigenetic machinery must play an important role in this process
of gradual transformation and may be modulated by the cellular
state and further exposures to different HCC risk factor(s) [4,19].
In most cases, the effects of histone modifications are more
complex and could only be explained by crosstalk between them,
wherein specific combinations of histone modifications affect the
accumulation and function of the histone-modifying enzymes,
DNA repair factors, transcription factors and chromatin remodel-
Z. Herceg, A. Paliwal / Mutation Research 727 (2011) 55–61
ing complexes. These interactions/crosstalk play an important role
in collectively regulating the critical chromatin functions and thus
avoiding genomic instability and oncogenic transformation. Crosstalk between histone modifications could be a result of modifications occurring on the same residue (in situ), on the same histone
(in cis), or on different histones (in trans) [8–10,49]. At present
there are no conclusive reports providing unequivocal support for
HCC-specific histone modification crosstalk. However, it remains
possible that different risk factor exposures and environmental
cues may affect expression of different histone modification
machineries and as a result different histone modifications or
crosstalk between different histone modifications may be modulated, resulting in HCC initiation and progression.
4. Noncoding RNAs (micro and long noncoding RNAs) in HCC
The most recent mechanism of epigenetic inheritance involves
RNAs, which in the form of either microRNAs (microRNAs or miRs)
or long noncoding RNA (long ncRNA or lncRNAs) can alter gene
expression states in a heritable manner. miRs are a class of small
RNA molecules that regulate gene expression [8,12,32]. Their
activity is a result of duplex formation between the miR and the 30
untranslated region (UTR) of target mRNAs. This results in
translational silencing by either mRNA degradation or translation
blocking. Several recent studies have implicated miR alterations in
different steps of hepatocellular carcinoma development and
metastatic progression (Table 1). In HCC several miRs are
deregulated, some of which function as oncogenes by inhibiting
apoptosis (miR-221), promoting cell invasion (miR-9), or silencing
c-Met/uPA-expression, thereby inhibiting migration and proliferation (miR23b). miR-101, 195, 122 and-338 have a tumor
suppressor gene-like function and are silenced in HCC. Downregulation of miR-122 has been reported to correlate with
suppression of the hepatic phenotype and gain of metastatic
properties. miR-152, miR-602 and miR-143 show HBV infectionspecific expression and regulate important cellular genes including
DNMT1, RASSF1A and FNDC3B affecting pathways related to cell
death, DNA damage, recombination, and signal transduction
[15,27,29,30]. miR-122 and miR-196 show HCV infection-specific
expression and regulate HMOX1/Bach1 and HCV genome expression [34,35]. These findings suggest that miRs could become novel
molecular targets for HCC treatment [8,32,50].
In addition to the well-characterized microRNAs, long ncRNAs
are also emerging as important regulatory molecules in tumorsuppressor and oncogenic pathways. Recent studies have provided
mechanistic insight into long ncRNAs that regulate key cancer
pathways at a transcriptional, post-transcriptional and epigenetic
level. For example, it is now well established that some long
ncRNAs such as XIST, HOTAIR, AIR and KCNQ1OT1 interact with
chromatin-remodeling complexes targeting them to specific genes
to exert their functions [32,50]. The oncogenic long ncRNAs may
thus hijack the epigenetic machinery to reshape the epigenetic
landscape leading to cancer.
5. Epigenetics-based therapy for HCC
Unlike genetic changes, epigenetic alterations are reversible
and thus have emerged as attractive molecular targets for
therapeutic intervention. Given the involvement of epigenetic
mechanisms in the development of hepatocellular carcinoma,
many resources have been mobilized to develop different
therapeutic approaches known as ‘‘epigenetic therapies’’ [2].
Currently, these approaches are directed at modifying DNA
methylation profiles and histone modification states in liver
cancer cells, and are based on specific properties of various
chemical agents affecting the activity of molecules (enzymes)
59
involved in the establishment and maintenance of epigenetic
marking. These epigenetic drugs consist of demethylating agents
and histone deacetylase inhibitors (HDACin). Both are able to reexpress epigenetically silenced genes, either by demethylation of
methylated promoter regions or by histone acetylation. Several
novel compounds (including 5-azacytidine (Vidaza), 5-aza-dC
(decitabine), MS-275, SAHA, Tributyrin, Valproic Acid) have been
tested preclinically in HCC and other cancers and show
promising results when used in combination therapy. The novel
HDAC in LBH589 is now being tested in combination with
sorafenib (a multi kinase inhibitor currently used in clinics).
However, despite the promise of epigenetic therapy, several
concerns need to be addressed before these epigenetic modulators can be fully exploited in clinics. These drugs lack
isoenzyme selectivity and require high doses, resulting in toxic
effects, and thus remain of limited therapeutic value [2,19,51].
The potential of antagomirs or reconstitutive miR compounds in
the treatment of HCC is also appealing and many preclinical
studies are already underway.
6. Conclusions and future directions
Aberrant epigenetic events play an important role in the onset
and progression of hepatocellular carcinoma, and have been
associated with all HCC subtypes. At the cellular level, aberrant
epigenetic events influence critical cellular events (i.e., gene
expression, DNA repair and cell cycle), which are further
modulated by risk factor exposures and thus define the severity/
subtype of HCC. The epigenetic events (DNA methylation, histone
modifications and non-coding RNAs), being specific to different
risk factor exposures, form an epigenetic signature with the
potential to serve as an important biomarker for early detection
and prevention of HCC [12,32,42]. However, although different
epigenetic events have been described/studied separately, all
epigenetic events are likely interdependent and collectively define
the epigenetic state of an individual cell in a given tissue for each
individual. Examples of the crosstalk between different epigenetic
modifications and their roles in the regulation of cellular processes
and tumorigenesis are becoming more evident and remain
important for a better mechanistic understanding and development of epigenetics-based therapeutic regimes.
Significant progress in the field of cancer epigenetics has
enhanced our understanding of the molecular mechanisms in
different cellular processes and in abnormal events involved in
carcinogenesis. Unlike genetic events, epigenetic events are
reversible, and thus hold better promise for therapeutic interventions. Epigenetic changes are present in almost every HCC subtype,
and different HCCs harbor specific ‘epigenetic signatures’. Recent
identification of DNA methylation in the HBV genome suggests
that it might be an important mechanism regulating transcription
and replication of the HBV virus [8,52]. However, the exact impact
of the observed methylation on the function of the HBV genome
remains unknown. Furthermore, it would be of interest to
investigate possible epigenetic mechanisms by which HBV
infection and integration of the viral genome may promote
hepatocarcinogenesis (Fig. 2). Future studies should also address
whether epigenetic changes induced by HBV and/or HCV infection
promote HCC development by inducing direct deregulation of
epigenetic states or if these changes are consequences of the
activation of inflammatory pathways. In order to enable the
development of new cancer therapies, more systematic studies,
involving different HCC subtypes at the genomic, epigenomic and
transcriptomic levels are necessary. A large number of genomewide methods and recent developments in novel sequencing
technologies should probably make these studies feasible in the
next few years.
60
Z. Herceg, A. Paliwal / Mutation Research 727 (2011) 55–61
Conflict of interest
Neither of the authors or the authors’ institutions has a financial
or other relationship with other people or organizations that may
inappropriately influence the authors’ work or this review.
Acknowledgments
The work in the Epigenetics Group at the International Agency
for Research on Cancer (Lyon, France) is supported by grants from
l’Agence Nationale de Recherche Contre le Sida et Hépatites Virales
(ANRS, France), l’Association pour la Recherche sur le Cancer (ARC),
France; and la Ligue Nationale (Française) Contre le Cancer, France
(to Z.H.). The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
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