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.

Abstract

UNLABELLED:

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.

• Authors: Kwang Hwa Jung, Ji Heon Noh, Jeong Kyu Kim, Jung Woo Eun, Hyun Jin Bae, Young Gyoon Chang, Min Gyu Kim, Won Sang Park, Jung Young Lee, Sang-Yeop Lee, In-Sun Chu, Suk Woo Nam
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 56 Issue 2 Pg. 644-57 (Aug 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22392728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• RNA, Small Interfering
• JNK Mitogen-Activated Protein Kinases
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (physiology)
• Beclin-1
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (physiology)
• Genes, Tumor Suppressor (physiology)
• Hep G2 Cells
• Histone Deacetylase 6
• Histone Deacetylases (genetics, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Liver Neoplasms (genetics, metabolism, pathology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prognosis
• RNA, Small Interfering (genetics)
• Transplantation, Heterologous