title: Down-regulation of deacetylase HDAC6 inhibits the melanoma cell line A375.S2 growth through ROS-dependent mitochondrial pathway.
abstract: Previous studies have shown that histone deacetylase 6 (HDAC6) plays critical roles in many cellular processes related to cancer. However, its biological roles in the development of melanoma remain unexplored. Our aim was to investigate whether HDAC6 has a biological role in human melanoma development and to understand its underlying mechanism. In the present study, HDAC6 expression was up-regulated in melanoma tissues and cell lines. Knockdown of HDAC6 significantly inhibited the proliferation and colony formation ability of A375.S2 cells, promoted cell arrest at G0/G1 phase and apoptosis. Additionally, western blotting assay showed that HDAC6 silencing suppressed Bcl-2 level and enhanced Bax level, then activated caspase-9 and caspase-3, and further activated the release of cytochrome c from mitochondria to cytoplasm, finally induced cell apoptosis involving the mitochondrial pathway. Knockdown of HDAC6 triggered a significant generation of ROS and disruption of mitochondrial membrane potential (MMP). Furthermore, ROS inhibitor, NAC reduced HDAC6 siRNA-induced ROS production, and blocked HDAC6 siRNA-induced loss of MMP and apoptosis. NAC also significantly blocked HDAC6 siRNA-induced mtDNA copy number decrease and mitochondrial biogenesis and degradation imbalance. In conclusion, the results showed that knockdown of HDAC6 induced apoptosis in human melanoma A375.S2 cells through a ROS-dependent mitochondrial pathway.
authors.affiliation: Department of Medical Oncology, Shaanxi Provincial People's Hospital, The Third affiliated Hospital of the School of Medicine Xi'an JiaoTong University, Xi'an, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Medical Oncology, Shaanxi Provincial People's Hospital, The Third affiliated Hospital of the School of Medicine Xi'an JiaoTong University, Xi'an, P. R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Medical Oncology, Shaanxi Provincial People's Hospital, The Third affiliated Hospital of the School of Medicine Xi'an JiaoTong University, Xi'an, P. R. China.
authors.forename: Gai-li
authors.initials: GL
authors.lastname: An
authors.affiliation: Department of Medical Oncology, Shaanxi Provincial People's Hospital, The Third affiliated Hospital of the School of Medicine Xi'an JiaoTong University, Xi'an, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: He
mesh_terms: D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014410:Tumor Stem Cell Assay
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D020782:Matrix Metalloproteinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases