Abstract 5134: Histone deacetylase 8 is a novel chromatin modulator in NAFLD-associated hepatocarcinogenesis (2014)

Abstract Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome including obesity and diabetes which elevate the risk of hepatocellular carcinoma (HCC). Emerging evidence suggests that epigenetics converts alterations in nutrient and metabolism into heritable pattern of gene expression. However, the role of epigenetic gene regulation in NAFLD-associated HCC remains to be defined (ref 1). Here we identified and validated novel chromatin modulators in NAFLD-associated hepatocarcinogenesis. Using customized real-time PCR arrays that contain 117 chromatin remodeling factors and modification enzymes, histone deacetylase 8 (Hdac8) mRNA expression was identified to be significantly up-regulated in HCC compared to tumor-adjacent and normal liver tissues in both diet- and genetic-induced obesity murine models (p&amp;lt;0.01 and &amp;lt;0.05 for high fat diet and db/db models, respectively). Over-expression of Hdac8 was validated by independent quantitative RT-PCR and Western blot analyses. Immunohistochemistry revealed cytoplasmic Hdac8 localization in the hepatocytes of normal liver tissue, while distinct nuclear Hdac8 expression was predominant in NAFLD-associated HCC. In human samples, 74.2% of NAFLD-associated HCC tissues displayed strong HDAC8 expression compared to tumor-adjacent tissues (p&amp;lt;0.001). In contrast, no significant HDAC8 up-regulation was found in hepatitis B virus-associated HCC, suggesting an etiology-specific over-expression pattern. Functional studies using both ectopic expression and pharmacological inhibition demonstrated growth enhancing functions for HDAC8, establishing the role of chromatin modulator in NAFLD-associated hepatocarcinogenesis. Up-regulation of HDAC8 is associated with suppressed AKT activity which is known to promote glucose production and insulin resistance in vitro and in vivo, indicating that HDAC8 may aggravate NAFLD progression through inhibiting insulin sensitivity. Further elucidation of the epigenetic regulation by HDAC8 will lead to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways in NAFLD-associated HCC. This study was supported by a Focused Investments Scheme - Scheme B (High Promise Initiatives) (Ref. No.: fis1112/0674/12yc) of the Chinese University of Hong Kong, a National Natural Science Foundation of China (Ref. No.: 373492), and a Theme-based Research Scheme (Ref. No.: T12-403/11) of the Hong Kong Research Grants Council. Reference: Tian Y, Wong VW, Chan HL, Cheng AS. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin Cancer Biol. 2013; 23:471-82. Note: This abstract was not presented at the meeting. Citation Format: Yuan Tian, Ka F. To, Paul B. s. Lai, Yue S. Cheung, Vincent Wai-Sun Wong, Henry Lik-Yuen Chan, Alfred Sze-Lok Cheng. Histone deacetylase 8 is a novel chromatin modulator in NAFLD-associated hepatocarcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5134. doi:10.1158/1538-7445.AM2014-5134