HDAC6型
自噬
癌症研究
组蛋白脱乙酰基酶
程序性细胞死亡
异位表达
组蛋白脱乙酰酶抑制剂
细胞生长
生物
细胞周期
癌细胞
激酶
癌症
细胞凋亡
细胞生物学
化学
细胞培养
组蛋白
生物化学
基因
遗传学
作者
Kwang Hwa Jung,Ji Heon Noh,Jeong Kyu Kim,Jung Woo Eun,Hyun Jin Bae,Young Gyoon Chang,Min Kim,Won Sang Park,Jung Young Lee,Sang Yeop Lee,In Sun Chu,Suk Woo Nam
出处
期刊:Hepatology
[Wiley]
日期:2012-06-11
卷期号:56 (2): 644-657
被引量:87
摘要
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.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.
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