title: Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma.
abstract: Melanoma, the most aggressive form of skin cancer, is often fatal if not treated early. Therefore, novel target-based strategies are required to combat this neoplasm. The objective of this study was to determine the role and functional significance of the mitochondrial sirtuin 3 (SIRT3) in melanoma. We found that compared with normal primary and immortalized human melanocytes, SIRT3 is significantly overexpressed in multiple human melanoma cells at mRNA and protein levels. Further, employing human tissue microarray, we found that SIRT3 is significantly upregulated in clinical melanoma tissues, compared with melanocytic nevi tissues. Furthermore, a short hairpin RNA-mediated knockdown of SIRT3 in human melanoma cells resulted in (i) a decrease in cellular proliferation, colony formation, and cellular migration; (ii) induction of senescence as shown by an increase in senescence-associated beta-galactosidase activity and formation of senescence-associated heterochromatin foci as well as an increase in mRNA and protein levels of p16(INK4a) and p21(Waf1); (iii) G1-phase arrest of the cell cycle; and (iv) decreases in mRNA and protein levels of cyclins (D1, E1) and cyclin-dependent kinases (2, 4, and 6). Conversely, forced exogenous overexpression of SIRT3 promoted an increase in proliferative potential of Hs294T melanoma cells and normal immortalized Mel-ST melanocytes. Finally, we found that SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model in vivo. To our knowledge, this is the first study supporting the pro-proliferative function of SIRT3 in melanoma.
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Nihal
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Chandra K
authors.initials: CK
authors.lastname: Singh
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA; William S. Middleton VA Medical Center, Madison, Wisconsin, USA. Electronic address: nahmad@wisc.edu.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009506:Nevus / Q000378:metabolism; D010641:Phenotype; D056566:Sirtuin 3 / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D001616:beta-Galactosidase; C466093:SIRT3 protein, human; D056566:Sirtuin 3