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Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas

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Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas Published OnlineFirst April 13, 2010; DOI: 10.1158/0008-5472.CAN-09-2913 Tumor and Stem Cell Biology Cancer Research Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas Sandy Giuliano1,2, Yann Cheli1,2, Mickaël Ohanna1,2, Caroline Bonet1,2, Laurent Beuret1,2, Karine Bille1,2, Agnès Loubat2,4, Véronique Hofman2,5, Paul Hofman2,5, Gilles Ponzio2,4, Philippe Bahadoran3, Robert Ballotti1,2, and Corine Bertolotto1,2 Abstract Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling ob- served in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, se- nescence, 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 G0-G1 growth arrest. Interestingly, decreased MITF expression has been described in senescent melano- cytes, 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 sus- tained growth arrest. Further, we show that MITF-silenced cells engage a DNA damage response (DDR) sig- naling 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. Cancer Res; 70(9); 3813–22. ©2010 AACR. Introduction advanced melanoma tumors, regulates MITF expression and activity (2). Further, BRAF cooperates with MITF to The M isoform of microphthalmia-associated transcrip- transform immortalized melanocytes (2). In line with this, tion factor (MITF), which is specifically expressed in the me- MITF expression has been associated with resistance to lanocyte lineage, is critical for melanocyte homeostasis and chemotherapy and correlates with unfavorable prognosis melanoma development. Several proteins that contribute to (2, 3). These observations suggest that MITF may function cell migration/invasion (DIA1 and c-MET), survival (BCL2, as a lineage-specific “addictive oncogene” in melanoma cells. HIF1a, c-MET,andML-IAP), and proliferation [cyclin-dependent Melanoma cells exposed to chemotherapeutic drugs reveal kinase 2 (CDK2)] have been identified as MITF target genes a reduction in MITF expression, suggesting that MITF brings (1). Further, a genetic amplification of MITF has been found important melanoma proliferative and survival advantages in 10% to 20% of melanomas and has been associated with (4). Consistently, inhibition of MITF expression induces a a decreased 5-year survival (2). Additionally, BRAF, whose V600E G -G growth arrest of melanoma cells (5–7). MITF has been gene exhibits oncogenic mutation (BRAF ) in >60% of 0 1 also involved in the control of melanoma survival through the control of BCL2 or BIRC7 (8, 9), but MITF silencing only Authors' Affiliations: 1Institut National de la Sante et de la Recherche marginally causes apoptosis (8, 10). In addition to apoptosis, Medicale U895, Team 1, Biology and pathology of melanocytes: from cutaneous pigmentation to melanoma; 2University of Nice Sophia- senescence is another cellular failsafe program that counter- Antipolis, UFR médecine; 3CHU NICE, Department of Dermatology; acts excessive mitogenic signaling observed in cancer cells. 4Institut National de la Sante et de la Recherche Medicale U634; The role of MITF in the control of the senescence program 5ERI21/EA 4319 and Human Biobank, Nice, France has never been studied thus far. However, a decreased MITF Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). expression has been observed in conditions that promote se- nescence of melanocytes (11). These observations prompted M. Ohanna and Y. Cheli contributed equally to this work. us to investigate whether MITF might control senescence of Corresponding Author: Corine Bertolotto, Institut National de la Sante et de la Recherche Medicale U895, 151 Route Saint Antoine de Ginestière, melanocytic cells. Nice 06204, France. Phone: 33-4-93-37-76-99; Fax: 33-4-93-37-76-98; Here,wereportthatlong-termsuppressionofMITFin E-mail: [email protected]. melanoma cells is associated with typical hallmarks of senes- doi: 10.1158/0008-5472.CAN-09-2913 cence, including enlarged and flattened cell morphologies, in- ©2010 American Association for Cancer Research. crease in cell granularity, acidic β-galactosidase staining, www.aacrjournals.org 3813 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst April 13, 2010; DOI: 10.1158/0008-5472.CAN-09-2913 Giuliano et al. change in chromatin structure associated with formation of was used to histochemically detect β-galactosidase activity heterochromatin foci, and cessation of proliferation. We at pH 6. Senescence-associated β-galactosidase (SA-β-Gal) show that the senescence program triggered by MITF silenc- activity results in a cytoplasmic blue staining that can be ing operates via a DNA damage response (DDR), leading to visualized by light microscopy. The percentage of means ataxia-telangiectasia mutated (ATM), H2AX, p53-binding and SDs were derived from counting 100 cells in duplicate protein 1 (53BP1), and CHK2 activation and ultimately re- plates after 96 hours. sulting in p53 phosphorylation and stabilization. Finally, Immunofluorescence and confocal microscopy. Immu- our findings show that the DDR machinery is critically re- nofluorescence experiments were carried out as previously quired, as pharmacologic inhibition and genetic ablation of described (14) and examined with a Zeiss Axiophot micro- ATM, CHK2, or p53 efficiently bypass the senescence pro- scope equipped with epifluorescence illumination or under gram mediated by MITF depletion. oil immersion with a Leica TCS SP2 confocal microscope. Therefore, MITF is critically required to prevent senes- Representative experiments are shown. cence and favor melanoma cell proliferation. Our results, Western blot assays. Western blots were carried out as which uncover the existence of a melanocyte-specific se- previously described (15). Briefly, cell lysates (30 μg) were nescence program, make MITF and p53 potential therapeu- separated by SDS-PAGE, transferred onto a polyvinylidene di- tic targets and open new perspectives in the treatment of fluoride membrane, and then exposed to the appropriate melanoma. antibodies. Proteins were visualized with the enhanced chemiluminescence system. The Western blots shown are Materials and Methods representative of at least three independent experiments. For measurement of secreted PAI-1, the culture medium Cell cultures. Human 501 mel, WM9, and Skmel28 mela- was replaced by serum-free medium for 48 hours and cells noma cells and mouse B16 melanoma cells were grown in were next precipitated with acetone. DMEM supplemented with 7% FCS and 100 units/mL peni- Chromatin immunoprecipitation assay. Chromatin cillin/50 μg/mL streptomycin at 37°C in a humidified atmo- immunoprecipitation (ChIP) assay was performed using sphere containing 5% CO2. anti-p53 antibody and the ChIP assay kit (Upstate). Anti- Transient transfection of small interfering RNA. Briefly, mouse IgG was used as controls. The primers for PAI-1 a single pulse of 50 nmol/L of small interfering RNA (siRNA) were 5′-GACACAGGCAGAGGG-3′ (forward) and 5′- was administrated to the cells at 50% confluency by transfec- GTGGGCCACTGCCTCC-3′ (reverse), with size for PCR pro- tion with 5 μL Lipofectamine RNAiMAX in Opti-MEM for ducts of 272 bp. The primers for glyceraldehyde-3-phosphate the time indicated in the figure legends. Control and MITF dehydrogenase (GAPDH) were 5′-TACTAGCGGTTT- siRNAs were previously described (12). A second MITF siRNA TACGGGCG-3′ (forward) and 5′-TCGAACAGGAGGAGCAGA- sequence (siMi2) described elsewhere was also used to rule GAGCGA-3′ (reverse), with size for PCR products of 160 bp. out the risk of off-target effects (5). p53 siRNA was from Statistical analysis. Data are presented as the average ± Santa Cruz Biotechnology. SDandwereanalyzedbyStudent'st test using Microsoft Growth curves. Cells (20 × 103) were seeded in six-well Excel software. P ≤ 0.05 was considered significant. dishes and transiently transfected the following day with control or MITF siRNA. Cells were next detached from days Results 2 to 6 and manually counted in triplicate with a hemocytom- eter to assess cell proliferation. The experiment was per- MITF suppression triggers senescence of melanoma formed three times. cells. We observed that hydroxyurea, a chemotherapeutic Luciferase reporter assays. 501 mel melanoma cells drug, blocked human 501 mel melanoma cell growth and were transiently transfected as previously described using led to morphologic changes that were associated with a stim- the Lipofectamine reagent (Invitrogen; ref. 13). Briefly, cells ulation of the SA-β-Gal activity, a widely used biomarker
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