Mini-reviewEpigenetic mechanisms in hepatocellular carcinoma: How environmental factors influence the epigenome
Introduction
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 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], [2], [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 β-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 factor-associated 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], [8], [9], [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].
Section snippets
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], [8], [9], [11], [12].
Aberrant DNA methylation changes have been reported to be specific to the cancerous tissue making it possible to
Aberrant histone modification changes in HCC
Recent studies have revealed the importance of histone-modifying 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 post-translational modifications of histone proteins. The N-terminal tails of nucleosomal histones are subject to different
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 3′ untranslated region (UTR) of target mRNAs. This results in translational silencing by either mRNA degradation
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
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
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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