title: Nuclear HDAC6 inhibits invasion by suppressing NF-κB/MMP2 and is inversely correlated with metastasis of non-small cell lung cancer.
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.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Peng
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, Taiwan.
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Dai
authors.affiliation: Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Yow-Ling
authors.initials: YL
authors.lastname: Shiue
authors.affiliation: Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, Taiwan.
authors.forename: Yao-Tsung
authors.initials: YT
authors.lastname: Yeh
mesh_terms: D000107:Acetylation; D000368:Aged; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000201:enzymology*; D049109:Cell Proliferation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; MMP2; NF-κB; lung cancer; metastasis