Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas.
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.
Giuliano
Sandy
S
Institut National de la Sante et de la Recherche Medicale U895, University of Nice Sophia-Antipolis, Nice, France.
Cheli
Yann
Y
Ohanna
Mickaël
M
Bonet
Caroline
C
Beuret
Laurent
L
Bille
Karine
K
Loubat
Agnès
A
Hofman
Véronique
V
Hofman
Paul
P
Ponzio
Gilles
G
Bahadoran
Philippe
P
Ballotti
Robert
R
Bertolotto
Corine
C
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
D051739:Microphthalmia-Associated Transcription Factor; D016159:Tumor Suppressor Protein p53