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; Yao-Tsung Yeh

doi:10.18632/oncotarget.4749

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

Oncotarget. 2015 Oct 6;6(30):30263-76. doi: 10.18632/oncotarget.4749.

Authors

Chih-Jen Yang^{1

2

3}, Yu-Peng Liu^{4

5}, Hong-Ying Dai⁶, Yow-Ling Shiue⁷, Chia-Jung Tsai⁷, Ming-Shyan Huang^{1

2}, Yao-Tsung Yeh^{8

6}

Affiliations

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, Taiwan.
⁷ Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁸ Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Abstract

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.

Keywords: HDAC6; MMP2; NF-κB; lung cancer; metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Aged
Binding Sites
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Carcinoma, Non-Small-Cell Lung / enzymology*
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / secondary
Carcinoma, Non-Small-Cell Lung / therapy
Cell Line, Tumor
Cell Movement*
Cell Nucleus / enzymology*
Cell Proliferation
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Histone Deacetylase 6
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Humans
Kaplan-Meier Estimate
Lung Neoplasms / enzymology*
Lung Neoplasms / genetics
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Lung Neoplasms / therapy
Male
Matrix Metalloproteinase 2 / genetics
Matrix Metalloproteinase 2 / metabolism*
Middle Aged
NF-kappa B / metabolism*
Neoplasm Invasiveness
Promoter Regions, Genetic
Proportional Hazards Models
Signal Transduction
Time Factors
Transcription Factor RelA / metabolism
Transfection

Substances

Biomarkers, Tumor
NF-kappa B
RELA protein, human
Transcription Factor RelA
MMP2 protein, human
Matrix Metalloproteinase 2
HDAC6 protein, human
Histone Deacetylase 6
Histone Deacetylases