Histone deacetylase 6 functions as a tumor suppressor by... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-terminal kinase-mediated beclin 1-dependent autophagic cell death in liver cancer

Jung, Kwang Hwa1,2; Noh, Ji Heon1,2; Kim, Jeong Kyu1,2; Eun, Jung Woo1,2; Bae, Hyun Jin1,2; Chang, Young Gyoon1,2; Kim, Min Gyu1,2; Park, Won Sang1,2; Lee, Jung Young1,2; Lee, Sang-Yeop3; Chu, In-Sun3; Nam, Suk Woo1,2,*,a

1_Department of Pathology, College of Medicine and Functional RNomics Research Center, Catholic University of Korea, Seoul, South Korea_

2_Functional RNomics Research Center, Catholic University of Korea, Seoul, South Korea_

3_Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea_

*Address reprint requests to: Department of Pathology, College of Medicine and Functional RNomics Research Center, Catholic University of Korea, Banpo-dong #505, Seocho-gu, South Korea 137-701

Email:[email protected]

Received 24 October 2011; Accepted 25 February 2012

Grant sponsor: National Research Foundation of Korea (NRF); Grant sponsor: Korean government (MEST); Grant Number: 2011-0010705; Grant sponsor: Public Welfare & Safety program through the National Research Foundation of Korea (NRF); Grant sponsor: Ministry of Education, Science and Technology; Grant Number: 2010-0020764; Grant sponsor: Korean Ministry of the Environment via “Converging Technology Project,” and by a grant from “KRIBB Research Initiative Program.”.

Potential conflict of interest: Nothing to report.

a_fax: +82-2-537-6586_

Abstract

Ubiquitin-binding histone deacetylase 6 (HDAC6) is uniquely endowed with tubulin deacetylase activity and plays an important role in the clearance of misfolded protein by autophagy. In cancer, HDAC6 has become a target for drug development due to its major contribution to oncogenic cell transformation. In the present study we show that HDAC6 expression was down-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients, and that low expression of HDAC6 was significantly associated with poor prognosis of HCC patients in 5-year overall, disease-free, and recurrence-free survival. Notably, we observed that ectopic overexpression of HDAC6 suppressed tumor cell growth and proliferation in various liver cancer cells, and elicited increased LC3B-II conversion and autophagic vacuole formation without causing apoptotic cell death or cell cycle inhibition. In addition, the sustained overexpression of HDAC6 reduced the in vivo tumor growth rate in a mouse xenograft model. It was also found that HDAC6 mediated autophagic cell death by way of Beclin 1 and activation of the LC3-II pathway in liver cancer cells, and that HDAC6 overexpression activated c-Jun NH2-terminal kinase (JNK) and increased the phosphorylation of c-Jun. In contrast, the induction of Beclin 1 expression was blocked by SP600125 (a specific inhibitor of JNK) or by small interfering RNA directed against HDAC6. Conclusion: Our findings suggest that loss of HDAC6 expression in human HCCs and tumor suppression by HDAC6 occur by way of activation of caspase-independent autophagic cell death through the JNK/Beclin 1 pathway in liver cancer and, thus, that a novel tumor suppressor function mechanism involving HDAC6 may be amenable to nonepigenetic regulation. (HEPATOLOGY 2012)