Epigenetic remodelling in human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination of genetic alterations mixed with epigenetic modifications.In HCC the patterns and frequencies of somatic variations change depending on the nearby chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutations. Epigenetics refers to heritable states of gene expression without alteration to the DNA sequence itself and, unlike genetic changes, the epigenetic modifications are reversible and affect gene expression more extensively than genetic changes. Thus, studies of epigenetic regulation and the involved molecular machinery are greatly contributing to the understanding of the mechanisms that underline HCC onset and heterogeneity. Moreover, this knowledge may help to identify biomarkers for HCC diagnosis and prognosis, as well as future new targets for more efficacious therapeutic approaches.In this comprehensive review we will discuss the state-of-the-art knowledge about the epigenetic landscape in hepatocarcinogenesis, including evidence on the diagnostic and prognostic role of non-coding RNAs, modifications occurring at the chromatin level, and their role in the era of precision medicine.Apart from other better-known risk factors that predispose to the development of HCC, characterization of the epigenetic remodelling that occurs during hepatocarcinogenesis could open the way to the identification of personalized biomarkers. It may also enable a more accurate diagnosis and stratification of patients, and the discovery of new targets for more efficient therapeutic approaches.

Keywords: Epidrugs; Epigenetics; HCC; Histone modifications; Methylation; Non-coding RNAs.

Fig. 1

The regulatory systems involved in the epigenetic landscape of human HCC. The epigenetic marks in HCC include histone tails modifications (acetylation, methylation, phosphorylation, etc.), non-coding RNAs, the presence of abnormal histone variants, and DNA promoter hypo- or hyper-methylation. The post-translational modifications of histone tails can modulate chromatin organization and alter the control of gene expression. Non-coding RNAs have emerged as regulators of chromatin structure. Non-canonical histone variants can affect chromatin remodelling and histone post-translational modifications. Alterations in the methylation of gene promoter regions cause altered gene expression

Fig. 2

Histone modifications in HCC. A Schematic representation of DNA-histone protein complexes. Human chromosomal DNA is made by looped chromatin fibers, tightly coiled around nucleosomes. Each nucleosome is composed of DNA and eight histone proteins (H2A, H2B, H3 and H4 dimers). B Schematic representation of the nucleosome. The main PTMs (methylation, acetylation, ubiquitination and phosphorylation) and their localization on the tails of the 4 main histones are reported. Enzymes involved in the mentioned modifications are listed in gray boxes. KMTs: Lysine Methyltransferases; KDMs: Lysine Demethylases; HATs: Histone Acetyltransferases; HDACs: Histone Deacetylases; E3s: E3 Ubiquitin Ligases; DUBs: Deubiquitinating enzymes. Created with BioRender.com (https://biorender.com7), accessed 10 Feb. 2022

Fig. 3

Epigenetic drugs in HCC. Schematic representation of the mechanisms of action of epigenetic drugs tested for HCC therapy