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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.
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https://www.hal.inserm.fr/inserm-02530589
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Mickaël Ohanna, Caroline Bonet, Karine Bille, Maryline Allegra, Irwin Davidson, et al.. SIRT1 promotes proliferation and inhibits the senescence-like phenotype in human melanoma cells. Oncotarget, Impact journals, 2014, 5 (8), pp.2085-95. ⟨10.18632/oncotarget.1791⟩. ⟨inserm-02530589⟩

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