Epigenetic mechanisms involved in hepatocellular carcinoma development and progression

Abstract

Hepatocellular carcinoma (HCC) typically develops in the context of chronic liver disease, where prolonged hepatocyte exposure to inflammation drives the synergistic accumulation of genetic and epigenetic alterations. Epigenetic regulation encompasses multiple mechanisms that govern the transcription machinery accessibility to DNA. This process is regulated by the addition and removal of covalent marks on chromatin, which can either affect DNA-histone interactions or serve as scaffolds for other proteins, among other mechanisms. Recent research has revealed that epigenetic alterations can disrupt chromatin homeostasis, redirecting transcriptional regulation to favour cancer-promoting states. Consequently, these alterations play a pivotal role in the acquisition of cancer hallmarks and provide insights into several biological processes involved in hepatocarcinogenesis. This review highlights the key epigenetic mechanisms underlying the development, progression and dissemination of HCC, with a particular focus on DNA methylation and histone post-translational modifications. This knowledge is relevant for guiding the development of innovative therapeutic approaches based on epigenetic modulators.

Keywords: Epigenetics; Gastrointestinal Cancer; Hepatocarcinogenesis; Hepatocellular Carcinoma.

Figure 1. DNA methylation and demethylation dynamics. (A) DNA methylation is maintained by DNMT1 on hemimethylated DNA after replication, while DNMT3A/3B catalyse de novo methylation on unmethylated DNA. In mammals, this modification is primarily found at CpG dinucleotides. (B) DNMTs use SAM as a methyl donor to convert cytosine into 5mC, while TET enzymes oxidise 5mC to 5hmC, 5fC and 5caC, which can be passively diluted through replication or actively removed via BER. 5caC, 5-carboxylcytosine; 5fC, 5-formylcytosine; 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; α-KG, α-ketoglutarate; BER, base excision repair; DNMTs, DNA methyltransferases; Me, methylation; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; Succ., succinate; TETs, Ten-Eleven Translocation enzymes.

Figure 2. Molecular dynamics of the most studied histone post-translational modifications (HPTMs) in hepatocellular carcinoma (HCC). Key modifications involved in HCC include lysine methylation and acetylation, regulated by KMTs/KDMs and HATs/HDACs, respectively, which influence chromatin accessibility and transcriptional activity. Additional PTMs, such as arginine methylation by PRMTs, phosphorylation by kinases, citrullination by PADs and ADP-ribosylation by PARPs also contribute to epigenetic remodelling. Some of these modifications, such as acetylation, citrullination, phosphorylation and ADP-ribosylation, alter the charge of the targeted amino acid residues, thereby affecting histone-DNA interactions and chromatin compaction. In contrast, methylation does not change the residue’s charge but can still influence chromatin structure by serving as docking sites for regulatory proteins. Ac, acetylation; Ac-CoA, acetyl-coenzyme A; ADPr, ADP-ribose; α-KG, α-ketoglutarate; BER, base excision repair; Cit, citrullination; CoA, coenzyme A; HATs, histone acetyltransferases; HDACs, histone deacetylases; JmjC, Jumonji C domain-containing demethylases; KDMs, lysine demethylases; KMTs, lysine methyltransferases; MARylation, mono-ADP-ribosylation; Me, methylation; PADs, peptidyl arginine deiminases; PARPs, poly(ADP-ribose) polymerases; PARylation, poly-ADP-ribosylation; Ph, phosphorylation; PRMTs, protein arginine methyltransferases; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; Succ., succinate.

Figure 3. Epigenetic aberrations in DNA methylation and HPTMs in hepatocellular carcinoma (HCC). (A) Global DNA hypomethylation contributes to genomic instability, while promoter hypermethylation leads to the silencing of tumour suppressor genes, promoting tumour progression. (B) HPTM writers, readers and erasers that are frequently overexpressed (red) or downregulated (blue) in HCC are depicted. Dysregulated expression of these epigenetic modulators disrupts histone modification patterns, leading to aberrant chromatin remodelling and altered accessibility. The resulting transcriptional reprogramming contributes to tumour growth, immune evasion, and therapy resistance. BRD, bromodomain-containing protein; CHD, chromodomain helicase DNA-binding protein; HAT, histone acetyltransferase; HDAC, histone deacetylase; HPTMs, histone post-translational modifications; KDM, lysine demethylase; KMT, lysine methyltransferase; MBD, methyl-CpG binding domain protein; Me, methylation; PRMT, protein arginine methyltransferase; SRA, SET and RING-associated domain-containing proteins; TSGs, tumour suppressor genes.