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

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Title
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)
K H Jung; J H Noh; J K Kim; J W Eun; H J Bae; Y G Chang; M G Kim; W S Park; J Y Lee; Sang Yoep Lee; In-Sun Chu; S W Nam
Bibliographic Citation
Hepatology, vol. 56, no. 2, pp. 644-657
Publication Year
2012
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.
ISSN
0270-9139
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/hep.25699
Type
Article
Appears in Collections:
Division of Biomedical Research > Genome Editing Research Center > 1. Journal Articles
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