Abstract 2073: Histone deacetylase 8 impairs insulin sensitivity and activates β-catenin signaling in NAFLD-associated hepatocellular carcinoma

Abstract

Abstract Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation tightly associated with central obesity, insulin resistance and other features of the metabolic syndrome that elevates the risk of hepatocellular carcinoma (HCC). Emerging evidence suggests that deregulated metabolic pathways can trigger epigenetic changes, thereby modifying the expression of critical genes associated with carcinogenesis (ref 1). However, the role of epigenetic regulation in NAFLD-associated HCC remains elusive. Here we identified and characterized a novel epigenetic regulator that contributes to insulin resistance and tumorigenesis in NAFLD. Gene expression profiling revealed histone deacetylase 8 (Hdac8) as the sole commonly up-regulated chromatin regulator in both murine dietary and genetic obesity-promoted HCC models. HDAC8 was up-regulated by the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1) via direct promoter binding. In a murine dietary-induced NAFLD model and an insulin resistant cell model, RNA interference and pharmacological inhibition by a selective HDAC8 inhibitor, PCI-34051, significantly rescued insulin sensitivity (p<0.05). Further functional characterization demonstrated the oncogenic activities of HDAC8 via inhibition of apoptosis, G2/M-phase arrest and stimulation of β-catenin-dependent proliferation. Mechanistically, HDAC8 was found to physically interact with the polycomb protein EZH2 to cooperatively repress Wnt antagonists via histone H4 deacetylation and H3 lyine 27 trimethylation (H3K27me3). To further validate the oncogenicity of HDAC8 in NAFLD-associated HCC, we infected lentivirus expressing short-hairpin RNA against Hdac8 in the dietary obesity-promoted HCC model. Notably, knockdown of HDAC8 restored the metabolic profiles (blood glucose, cholesterol, triglyceride and non-esterified fatty acid) to normal states and dramatically reduced hepatic tumorigenicity (p<0.01). In 24 pairs of human NAFLD-associated HCC specimens, SREBP-1, HDAC8, EZH2, H3K27me3 and active β-catenin were found to be concordantly up-regulated in tumors compared to non-tumor tissues. In conclusions, our findings demonstrated the functional significance of HDAC8 in NAFLD-associated hepatocarcinogenesis and unveiled the molecular basis for its regulation and oncogenicity, providing a strong impetus for therapeutic intervention against the rapidly rising incidence of HCC in obese and diabetic patients. Reference: 1. Tian Y et al., Semin Cancer Biol 2013 Citation Format: Yuan Tian, Ka F. To, Paul B.S. Lai, Yue S. Cheung, Jun Yu, Vincent W.S Wong, Henry L.Y. Chan, Alfred S.L. Cheng. Histone deacetylase 8 impairs insulin sensitivity and activates β-catenin signaling in NAFLD-associated hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2073. doi:10.1158/1538-7445.AM2015-2073