title: Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas.
abstract: Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling observed in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, senescence, which remains poorly understood in melanomas, can be viewed as a therapeutic alternative. Microphthalmia-associated transcription factor (MITF), in which its M transcript is specifically expressed in melanocyte cells, plays a critical role in melanoma proliferation, and its specific inhibition is associated with G(0)-G(1) growth arrest. Interestingly, decreased MITF expression has been described in senescent melanocytes, and we have observed an inhibition of MITF expression in melanoma cells exposed to chemotherapeutic drugs that induce their senescence. All these observations thereby question the role of MITF in controlling senescence in melanoma cells. Here, we report that long-term depletion of MITF in melanoma cells triggers a senescence program characterized by typical morphologic and biochemical changes associated with a sustained growth arrest. Further, we show that MITF-silenced cells engage a DNA damage response (DDR) signaling pathway, leading to p53 upregulation, which is critically required for senescence entry. This study uncovers the existence of a lineage-restricted DDR/p53 signaling pathway that is inhibited by MITF to prevent senescence and favor melanoma cell proliferation.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U895, University of Nice Sophia-Antipolis, Nice, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Giuliano
authors.forename: Yann
authors.initials: Y
authors.lastname: Cheli
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ohanna
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonet
authors.forename: Laurent
authors.initials: L
authors.lastname: Beuret
authors.forename: Karine
authors.initials: K
authors.lastname: Bille
authors.forename: Agnès
authors.initials: A
authors.lastname: Loubat
authors.forename: Véronique
authors.initials: V
authors.lastname: Hofman
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Gilles
authors.initials: G
authors.lastname: Ponzio
authors.forename: Philippe
authors.initials: P
authors.lastname: Bahadoran
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D004249:DNA Damage; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D016159:Tumor Suppressor Protein p53