Abstract 2865: Cytoplasmic deacetylase HDAC6 confers tumor suppressive potential through autophagic cell death in human hepatocellular carcinoma

Abstract

Abstract The histone modification and acetylation by histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been associated with chromatin decondensation and transcriptional activation and silencing. HDAC6, one of class II HDAC isotypes, is a cytosolic protein and microtubule-associated deacetylase that interacts with non-histone protein, including α-tubulin. HDAC6 is involved in autophagic degradation of the cells, but the underlying mechanism associated with carcinogenesis in solid tumors remains unclear. In this study, we investigated the expression levels of HDAC6 in human liver cancer cell lines and tissues. HDAC6 expression was analyzed by Western blot analysis in nine selected hepatocellular carcinomas (HCCs) and immunohistochemical staining was performed in paraffin-embedded samples from 32 liver cancers. HDAC6 expression was significantly down-regulated in the HCCs compared to corresponding normal tissues in nine selected tissue samples. Immunohistochemical analysis also showed commonly down-regulated HDAC6 expression in the HCCs. Thus, to investigate the HDAC6-induced anti-neoplastic potentials on liver cancer progression, we restored HDAC6 expression using gene transfection in human Hep3B liver cancer cell line. Over-expression of HDAC6 suppressed proliferation of liver cancer cells with decreased acetylation status of α-tubulin and exhibited the characteristics of autophagic degradation (autophagosome formation and the LC3-II generation) in Western blot and Electron Microscopy (EM) analysis. In addition, we found that over-expression of HDAC6 induced expression of autophagy-related gene Beclin 1, a key molecule of autophagosome formation. In contrast, knock-down of HDAC6 over-expressed cells could reduce the expression level of increased Beclin 1 and LC3-II with restoration of acetylated α-tubulin. Furthermore, in the xenograft mouse models, over-expression of HDAC6 significantly suppressed tumor growth and incidence of tumor formation. In conclusion, our results suggest that HDAC6-indued autophagic cell death provide a novel mechanism for the regulation of beclin1 and LC3 expression in liver cancer development and progression providing new therapeutic intervention in human hepatocellular carcinoma Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2011-2865