*Purpose: Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers and is characterized by an acquisition of multiple abnormal phenotypes driven by epigenetic alterations. Epigenetic changes including histone modifications are associated with uncontrolled cell growth and proliferation, and even initiation and progression of HCC from chronic inflammation with or without fibrosis in the liver. Among others, NASH and ASH are two major risk factors as both of them may develop cirrhosis and HCC if left untreated. Most of the existing clinical and experimental reports provide only a snapshot of abnormal histone modifications in HCC rather than their dynamic changes. This makes it difficult to elucidate the significance of these changes in the development of HCC. In the present study, we investigated the role of histone acetylation/methylation mediated alterations using in vitro cell line and high fat diet animal model of NASH-derived liver carcinogenesis.

*Methods: In vitro studies were done using hepatocellular carcinoma cell lines, HEP3B and SNU 475, treated with different doses of pNaKtide at different time points. C57BL/6 female mice were exposed to normal mouse chow (NMC), HFD and HFD± pNaKtide for 24 weeks. HCC mice were exposed to graded doses of pNaKtide. The acetylated and tri methylated H3K9 in cell lysates and liver homogenates were quantitatively measured by ELISA. Expression of H3acetylK9 and H3tri-methyl K9 proteins were performed by confocal-microscopy on immuno-stained livers from HCC and NASH. Significant differences among groups were established at p<0.05 using ANOVA/t-test.

*Results: The amount of acetylated and tri methylated H3K9 were found to be significantly increased in untreated hepatocellular carcinoma cells and were significantly decreased by pNaKtide treatment. In line with these in vitro results, the increased amount of acetylated and tri methylated H3K9 in the liver of NASH and HCC mice were found to be significantly decreased by pNaKtide administration. The immunofluorescence analysis of H3acetylK9 and H3tri-methyl K9 proteins further confirmed our findings.

*Conclusions: In summary, the pivotal role of concurrent activation of acetylation and tri methylation of H3K9 in the pathogenesis of NASH associated HCC, as evidenced by our findings, explore their potential for translation into therapeutics by epigenome reprogramming.

« Back to 2021 American Transplant Congress