Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Abstract

Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

Keywords: 5acC, 5-acetylcytosine; 5fC, 5-formylcytosine; 5hmC, 5-hydoxymethyl cytosine; 5mC, 5-methylcytosine; Acetyl-CoA, acetyl coenzyme A; BER, base excision repair; BRD, bromodomain; CDA, cytidine deaminase; CGI, CpG island; CIMP, CGI methylator phenotype; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DNMT, DNA methyltransferase; DNMTi, DNMT inhibitor; Epigenetics; FAD, flavin adenine dinucleotide; HAT, histone acetyltransferases; HCC, hepatocellular carcinoma; HDAC, histone deacetylase; HDACi, HDAC inhibitor; HDM, histone demethylase; HMT, histone methyltransferase; Hepatocellular carcinoma; KMT, lysine methyltransferase; LSD/KDM, lysine specific demethylases; NAFLD, non-alcoholic fatty liver disease; NK, natural killer; NPC, nasopharyngeal carcinoma; PD-L1, programmed cell death ligand-1; PD1, programmed cell death protein 1; PHD, plant homeodomain; PTM, post-translational modification; SAM, S-adenosyl-L-methionine; TDG, thymidine-DNA-glycosylase; TERT, telomerase reverse transcriptase; TET, ten-eleven translocation; TME, tumour microenvironment; TSG, tumour suppressor gene; Therapy; UHRF1, ubiquitin like with PHD and ring finger domains 1; VEGF, vascular endothelial growth factor; ncRNAs, non-coding RNAs; α-KG, α-ketoglutarate.

Fig. 1

Chromatin conformation and regulation of gene expression by epigenetic effectors acting on DNA and histones: epigenetic writers, erasers and readers. PHD, plant homeodomain.

Fig. 2

Alterations in epigenetic mechanisms during hepatocarcinogenesis. Ac, acetylation; HCC, hepatocellular carcinoma; Me, methylation; TETs, ten-eleven translocation enzymes; TSG, tumour suppressor gene.

Fig. 3

Drugs targeting epigenetic writers, erasers and readers in HCC therapy. 5mC, 5-methyl-cytosine; Ac, acetylation; BRDi, bromodomain inhibitor; DNMT, DNA methyltransferase; DNMTi, DNMT inhibitor; HCC, hepatocellular carcinoma; HDAC, histone deacetylase; HDACi, HDAC inhibitor; HDM, histone demethylase; HDMi, HDM inhibitor; HMT, histone methyltransferase; HMTi, HMT inhibitor; KMT, lysine methyltransferase; KMTi, KMT inhibitor; KDMi, lysine specific demethylase inhibitor; Me, methylation.