title: SIRT1 promotes proliferation and inhibits the senescence-like phenotype in human melanoma cells.
abstract: SIRT1 operates as both a tumor suppressor and oncogenic factor depending on the cell context. Whether SIRT1 plays a role in melanoma biology remained poorly elucidated. Here, we demonstrate that SIRT1 is a critical regulator of melanoma cell proliferation. SIRT1 suppression by genetic or pharmacological approaches induces cell cycle arrest and a senescence-like phenotype. Gain and loss of function experiments show that M-MITF regulates SIRT1 expression, thereby revealing a melanocyte-specific control of SIRT1. SIRT1 over-expression relieves the senescence-like phenotype and the proliferation arrest caused by MITF suppression, demonstrating that SIRT1 is an effector of MITF-induced proliferation in melanoma cells. Interestingly, SIRT1 level and activity are enhanced in the PLX4032-resistant BRAF(V600E)-mutated melanoma cells compared with their sensitive counterpart. SIRT1 inhibition decreases melanoma cell growth and rescues the sensibility to PLX4032 of PLX4032-resistant BRAF(V600E)-mutated melanoma cells. In conclusion, we provide the first evidence that inhibition of SIRT1 warrants consideration as an anti-melanoma therapeutic option.
authors.affiliation: INSERM, U1065 (équipe 1), Equipe labélisée Ligue Contre le Cancer, C3M, Nice, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ohanna
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonet
authors.forename: Karine
authors.initials: K
authors.lastname: Bille
authors.forename: Maryline
authors.initials: M
authors.lastname: Allegra
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.forename: Philippe
authors.initials: P
authors.lastname: Bahadoran
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lacour
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology*; D016922:Cellular Senescence / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D018613:Microscopy, Confocal; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000378:metabolism*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; C447939:SIRT1 protein, human; D056564:Sirtuin 1
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