Research Papers:

Nuclear HDAC6 inhibits invasion by suppressing NF-κB/MMP2 and is inversely correlated with metastasis of non-small cell lung cancer

Chih-Jen Yang _, Yu-Peng Liu, Hong-Ying Dai, Yow-Ling Shiue, Chia-Jung Tsai, Ming-Shyan Huang and Yao-Tsung Yeh

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Oncotarget. 2015; 6:30263-30276. https://doi.org/10.18632/oncotarget.4749

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Chih-Jen Yang1,2,3, Yu-Peng Liu5,6, Hong-Ying Dai7, Yow-Ling Shiue8, Chia-Jung Tsai8, Ming-Shyan Huang1,2, Yao-Tsung Yeh4,7

1Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

2Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

4Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

5Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

6Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan

7Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, Taiwan

8Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan

Correspondence to:

Yao-Tsung Yeh, e-mail: [email protected]

Ming-Shyan Huang, e-mail: [email protected]

Keywords: HDAC6, NF-κB, MMP2, metastasis, lung cancer

Received: March 03, 2015     Accepted: September 04, 2015     Published: September 15, 2015


Histone deacetylase 6 (HDAC6) is a unique member of the histone deacetylase family. Although HDAC6 is mainly localized in the cytoplasm, it can regulate the activities of the transcription factors in the nucleus. However, a correlation of intracellular distribution of HDAC6 with tumor progression is lacking. In this study, we found that a low frequency of nuclear HDAC6-positive cells in tumors was associated with distant metastasis and a worse overall survival in 134 patients with non-small cell lung cancer (NSCLC). Ectopic expression of wild-type HDAC6 promoted migration and invasion of A549 and H661 cells. However, the enforced expression of nuclear export signal-deleted HDAC6 inhibited the invasion but not the migration of both cell lines. The inhibitory effect of nuclear HDAC6 on invasion was mediated by the deacetylation of the p65 subunit of nuclear factor-κB, which decreased its DNA-binding activity to the MMP2 promoter, leading to the downregulation of MMP2 expression. Our findings indicated that the loss of nuclear HDAC6 may be a potential biomarker for predicting metastasis in patients with NSCLC.

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