Inhibition of the Cell Death Pathway in Nonalcoholic Steatohepatitis (NASH)-Related Hepatocarcinogenesis Is Associated with Histone H4 lysine 16 Deacetylation
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 ...Continue Reading
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Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma.
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