SIRT1 promotes proliferation and inhibits the senescence-like phenotype in human melanoma cells
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Mickaël Ohanna 1,2, Caroline Bonet1,2, Karine Bille1,2, Maryline Allegra1,2, Irwin Davidson3, Philippe Bahadoran2,4, Jean-Philippe Lacour2,4, Robert Ballotti1,2 and Corine Bertolotto1,2.
1, INSERM, U1065 (équipe 1), Equipe labélisée Ligue Contre le Cancer, C3M, Nice, France.
2, Université de Nice Sophia-Antipolis, UFR Médecine, Nice, France.
3, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
4, Centre Hospitalier Universitaire, Service de Dermatologie, Nice, France
Corine Bertolotto, email:
Keywords: melanoma, MITF, SIRT1, PLX4032, treatment
Received: February 7, 2014 Accepted:February 18, 2014 Published: February 19, 2014
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 BRAFV600E-mutated melanoma cells compared with their sensitive counterpart. SIRT1 inhibition decreases melanoma cell growth and rescues the sensibility to PLX4032 of PLX4032-resistant BRAFV600E-mutated melanoma cells. In conclusion, we provide the first evidence that inhibition of SIRT1 warrants consideration as an anti-melanoma therapeutic option.
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