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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
Author(s) -
Jung Kwang Hwa,
Noh Ji Heon,
Kim Jeong Kyu,
Eun Jung Woo,
Bae Hyun Jin,
Chang Young Gyoon,
Kim Min Gyu,
Park Won Sang,
Lee Jung Young,
Lee SangYeop,
Chu InSun,
Nam Suk Woo
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25699
Subject(s) - hdac6 , autophagy , cancer research , histone deacetylase , programmed cell death , ectopic expression , histone deacetylase inhibitor , cell growth , biology , cell cycle , cancer cell , kinase , cancer , apoptosis , microbiology and biotechnology , chemistry , cell culture , histone , biochemistry , genetics , gene
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. (H EPATOLOGY 2012)