Histone Deacetylase Inhibitors in the Treatment of Hepatocellular Carcinoma: Current Evidence and Future Opportunities

Abstract

Hepatocellular carcinoma (HCC) remains a major health problem worldwide with a continuous increasing prevalence. Despite the introduction of targeted therapies like the multi-kinase inhibitor sorafenib, treatment outcomes are not encouraging. The prognosis of advanced HCC is still dismal, underlying the need for novel effective treatments. Apart from the various risk factors that predispose to the development of HCC, epigenetic factors also play a functional role in tumor genesis. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone lysine residues of proteins, such as the core nucleosome histones, in this way not permitting DNA to loosen from the histone octamer and consequently preventing its transcription. Considering that HDAC activity is reported to be up-regulated in HCC, treatment strategies with HDAC inhibitors (HDACIs) showed some promising results. This review focuses on the use of HDACIs as novel anticancer agents and explains the mechanisms of their therapeutic effects in HCC.

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

“…In this study, we provide evidence that energy metabolism can direct epigenetic change and DNA damage across the genome, including to the earliest mutated gene in HCC. While acetylation changes and HDAC expression changes are known in HCC 20 and NAFLD 30 , the relationship between histone acetylation and DNA mutations at known HCC-driver genes has not been reported. Our focus on non-cancerous, pre-mutational hepatocytes provides insight into the priming steps of an increasingly common cancer which has a five-year survival of 19% 31 and is responsible for more than 700,000 attributable deaths per year worldwide 32 , and may explain why HCC risk increases in NAFLD patients from the early stages of steatosis.…”

“…Mutations in epigenetic modifier proteins are commonly found in cancer, even as the initiating mutation 17,18 . The potential therapeutic opportunity of this relationship in the context of histone acetylation is currently being tested with several clinical trials of pharmacological inhibitors of the writers, histone acetyltransferases (HATs), and erasers, histone deacetylases (HDACs) in a variety of cancers, including HCC 19,20 . These therapies aim to reverse epigenetic dysregulation in partially or fully developed cancers, after cancer-promoting DNA mutations have occurred, rather than at the initial pre-mutational stages that promote carcinogenesis.…”

RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality?

“…Interestingly, HDAC8 caused PKM2 to translocate to the nucleus and synergize with β-catenin transcription to upregulate the expression of cyclin D1 ( 98 ). SNALP based NPs have also been used to transport both HDAC1 and HDAC2 siRNA to induce apoptosis by upregulating p57/p27 expression, as well as downregulating bcl-2 expression ( 100 , 101 ) which is associated with a pro-survival effect in HCC ( 163 ). Another stabilized siRNA model demonstrated the synergistic effect between hTERT siRNA and Cisplatin in the suppression of HCC progression and indicated that the combination of hTERT-specific siRNA and cisplatin could be an effective therapy for HCC to promote cell cycle controls via G2/M and S phases thus inducing apoptosis ( 102 ).…”

Role of histone deacetylase inhibitors in diabetic cardiomyopathy in experimental models (Review)

“…of note, four of them have already been approved by the US Food and Drug administration (FDa) against hematological malignancies (14). additionally, their anticancer activity has been reported extensively in the literature, including colorectal, hepatocellular, pancreatic, breast, thyroid, lung, endometrial, and other cancers such as uveal and cutaneous melanoma (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Furthermore, their role appear to be crucial in fighting other diseases, including viral infections and both inflammatory and neurological disorders (28,29).…”