Inhibition of the Cell Death Pathway in Nonalcoholic Steatohepatitis (NASH)-Related Hepatocarcinogenesis Is Associated with Histone H4 lysine 16 Deacetylation

Aline De Conti,Igor P Pogribny,Volodymyr Tryndyak,Frederick A Beland,Sharon A Ross,Kostiantyn Dreval,Orish E Orisakwe

doi:10.1158/1541-7786.mcr-17-0109

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers, and its incidence is steadily increasing worldwide. Recent epidemiologic findings have suggested that the increased incidence of HCC is associated with obesity, type II diabetes mellitus, and nonalcoholic steatohepatitis (NASH); however, the mechanisms and the molecular pathogenesis of NASH-related HCC are not fully understood. To elucidate the underlying mechanisms of the development of NASH-related HCC, we investigated the hepatic transcriptomic and histone modification profiles in Stelic Animal Model mice, the first animal model of NASH-related HCC to resemble the disease pathogenesis in humans. The results demonstrate that the development of NASH-related HCC is characterized by progressive transcriptomic alterations, global loss of histone H4 lysine 20 trimethylation (H4K20me3), and global and gene-specific deacetylation of histone H4 lysine 16 (H4K16). Pathway analysis of the entire set of differentially expressed genes indicated that the inhibition of cell death pathway was the most prominent alteration, and this was facilitated by persistent gene-specific histone H4K16 deacetylation. Mechanistically, deacetylation of histone H4K16 was associated with downregulation of lysine acetyltransferase KAT8, which was driven by overexpression of its inhibitor nuclear protein 1 (Nupr1). The results of this study identified a reduction of global and gene-specific histone H4K16 acetylation as a key pathophysiologic mechanism contributing to the development of NASH-derived HCC and emphasized the importance of epigenetic alterations as diagnostic and therapeutic targets for HCC.Implications: Histone H4K16 deacetylation induces silencing of genes related to the cell death that occurred during the development of NASH-related HCC. Mol Cancer Res; 15(9); 1163-72. ©2017 AACR.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common human cancer [1] and the third leading cause of cancer-related deaths in the world [2]
Epigenetic alterations in a choline- and folate-deficient (CFD) model of nonalcoholic steatohepatitis (NASH) To investigate whether molecular alterations found in the livers of Stelic Animal Model (STAM) mice exist in another mouse models of NASH, we investigated the expression of nuclear protein 1 (Nupr1) and Kat8 genes, the protein level of KAT8 histone H4K16 acetyltransferase, gene expression of the same 21 differentially expressed cell death–related genes, and the status of their gene-specific histone H4K16ac in the livers of male C57BL/6J mice fed a CFD diet
To understand better the molecular pathogenesis of liver tumor development, transcriptomic and histone modification profiles were investigated at different stages of tumor development using the STAM mouse model of NASH-related HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common human cancer [1] and the third leading cause of cancer-related deaths in the world [2]. HCC commonly arises in humans with chronic liver disease caused by well-identified etiologic factors, including chronic hepatitis B and C viral infections, chemical exposure, and excessive alcohol consumption. In addition to these well-characterized risk factors, the results from comprehensive epidemiologic studies have dem-. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Aline de Conti and Kostiantyn Dreval contributed to this article.

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