Chromatin chronicles: Unlocking the therapeutic potential of histone modifiers in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents the primary liver cancer among adults with diverse tissue appearance, high disease severity, and negative treatment expectancy. The molecular heterogeneity, extensive invasion, and propensity for relapse of HCC present a substantial challenge for oncologists. Hepatoma cells display deregulated genomic pathways interacting with epigenetic modifications. Epigenetic changes are crucial in HCC research, serving as potential biomarkers for tumor classification, prognosis, and drug targeting. Histone PTMs and chromatin regulation control gene expression during malignant transformation and tumor progression. The development of HCC is influenced by the alteration in the expression of genes that encode acetyltransferases and deacetylases (KAT6A, SIRT2, SIRT7, HDAC4, 6, 9) and lysine and arginine methyltransferases (G9a, SUV39H1, and SETDB1). Furthermore, HCC cell lines exhibit an upregulation of proteins from the sumoylation pathway, such as E1 (SAE1), E2 (Ubc9) components, and a SUMO-specific protease (SENP1) and TGM2 from serotonylation respectively. The latest generation of HDAC inhibitors, protein arginine methyltransferase (PRMT) inhibitors, and bromodomain inhibitors are being studied in preclinical and clinical research for HCC treatment. The article provides an extensive breakdown of contemporary HCC epigenetic research focusing on histone modifications while exploring epigenetic therapy as an available treatment approach for HCC. This review is a summary on the existing knowledge on the various epigenetic mechanisms that shape HCC biology with a special focus on histone-modifying enzymes, newly identified epigenetic regulators, and their therapeutic potential.