SIRT1 promotes proliferation and inhibits the senescence-like phenotype in human melanoma cells.

// Mickael Ohanna 1,2 , Caroline Bonet 1,2 , Karine Bille 1,2 , Maryline Allegra 1,2 , Irwin Davidson 3 , Philippe Bahadoran 2,4 , Jean-Philippe Lacour 2,4 , Robert Ballotti 1,2 and Corine Bertolotto 1,2 . 1, INSERM, U1065 (equipe 1), Equipe labelisee Ligue Contre le Cancer, C3M, Nice, France. 2, Universite de Nice Sophia-Antipolis, UFR Medecine, Nice, France. 3, Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Universite de Strasbourg, Illkirch, France. 4, Centre Hospitalier Universitaire, Service de Dermatologie, Nice, France Correspondence: Corine Bertolotto, email: // Keywords : melanoma, MITF, SIRT1, PLX4032, treatment Received : February 7, 2014 Accepted :February 18, 2014 Published : February 19, 2014 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 -i nduced 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.