title: SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation.
abstract: Melanoma causes more deaths than any other skin cancer, and its incidence in the US continues to rise. Current medical therapies are insufficient to control this deadly neoplasm, necessitating the development of new target-based approaches. The objective of this study was to determine the role and functional significance of the class III histone deacetylase SIRT1 in melanoma. We have found that SIRT1 is overexpressed in clinical human melanoma tissues and human melanoma cell lines (Sk-Mel-2, WM35, G361, A375, and Hs294T) compared to normal skin and normal melanocytes, respectively. In addition, treatment of melanoma cell lines A375, Hs294T, and G361 with Tenovin-1, a small molecule SIRT1 inhibitor, resulted in a significant decrease in cell growth and cell viability. Further, Tenovin-1 treatment also resulted in a marked decrease in the clonogenic survival of melanoma cells. Further experiments showed that the anti-proliferative response of Tenovin-1 was accompanied by an increase in the protein as well as activity of the tumor suppressor p53. This increase in p53 activity was substantiated by an increase in the protein level of its downstream target p21. Overall, these data suggest that small molecule inhibition of SIRT1 causes anti-proliferative effects in melanoma cells. SIRT1 appears to be acting through the activity of the tumor suppressor p53, which is not mutated in the majority of melanomas. However, future detailed studies are needed to further explore the role and mechanism of SIRT1 in melanoma development and progression and its usefulness in melanoma treatment.
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Wilking
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Singh
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Nihal
authors.affiliation: Department of Pathology, University of Wisconsin, Madison, WI 53705, USA.
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. Electronic address: nahmad@wisc.edu.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000594735:tenovin-1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D013890:Thiourea
keywords: Melanoma; SIRT1; Tenovin-1; p21; p53
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