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.

The role of RNA modification in hepatocellular carcinoma

“…RNA modifications play a key role in regulating cell fate, an important regulator of HCC, in tumorigenesis and disease progression (Han et al, 2018;Pea et al, 2021;Braghini et al, 2022). The m6A, m7G, m5C, m1A, m3C, and ψ RNA modifications dynamically regulate the development of HCC, providing new strategies and possibilities for selecting possible therapeutic targets and investigating precisely directed intervention strategies for future HCC therapy (Tian et al, 2019;Bolatkan et al, 2022;Liu et al, 2022;Ren et al, 2022;Tong et al, 2022;Yu et al, 2022).…”

“…HCC has a poor prognosis, making it crucial to investigate the molecular mechanisms and therapeutic strategies underlying hepatocellular carcinogenesis (Llovet et al, 2008;Chen et al, 2015). It has been shown that hepatocellular carcinogenesis is regulated by complex genetic and epigenetic mechanisms with pathophysiological processes involving viral and non-viral factors and influenced by fatty liver, immune cell infiltration, and the tumor microenvironment (Ozen et al, 2013;Han et al, 2018;Pea et al, 2021;Braghini et al, 2022). A study using whole-genome and -exome sequencing analysis has shown that epigenetic regulation is the most unusual differential modifier in HCC, with aberrant RNA modifications leading to differential gene expression, affecting the HCC formation and progression (Schulze et al, 2015;Klingenberg et al, 2017;Chen et al, 2018).…”

Identification of a novel histone phosphorylation prognostic signature in hepatocellular carcinoma based on bulk and single-cell RNA sequencing

“…In recent years, histone modifications related to tumor formation and development have gradually attracted the attention of epigenetic researchers, and the increasing number of results indicate that tumors are often caused by histone modifications that affect their occurrence and prognosis ( 13 ). The epigenetic modifications offer ideal mechanisms for regulating gene expression and metabolic reprogramming.…”

Attempts to Detect Lipid Metabolites from a Single Cell Using Proton-Transfer-Reaction Mass Spectrometry Coupled with Micro-Scale Supercritical Fluid Extraction: A Preliminary Study

“…Immortalized cells such as HeLa, HepG2, and Huh-7 cells have been widely used by researchers in the molecular biological sciences [1][2][3][4][5][6][7][8] because they are essentially identical cells that never change. The use of such cells has contributed to the study of tumor tissue formation at the molecular level.…”