Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas
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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.
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MITF controls UVB-induced expression of pigmentation genes and DNA repair and proliferation genes in melanoma cells.
“MITF controls UVB-induced expression of pigmentation genes32 and DNA repair and proliferation genes in melanoma cells51,52.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [52]
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- Authors
- Giuliano, S., Cheli, Y., Ohanna, M., Bonet, C., Beuret, L., Bille, K., Loubat, A., Hofman, V., Hofman, P., Ponzio, G., Bahadoran, P., Ballotti, R., & Bertolotto, C.
- Affiliations
- Inserm (FR)
- Authors' Affiliations: 1Institut National de la Sante et de la Recherche Medicale U895, Team 1, Biology and pathology of melanocytes: from cutaneous pigmentation to melanoma; 2University of Nice Sophia-Antipolis, UFR médecine; 3CHU NICE, Department of Dermatology; 4Institut National de la Sante et de la Recherche Medicale U634; 5ERI21/EA 4319 and Human Biobank, Nice, France
- Corresponding author
- Bertolotto, Corine
- ORCID
- Venue
- Cancer Research
- Published
- 2010-04-28
- Volume
- 70
- Issue
- 9
- Pages
- 3813-3822
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2052677817
- Cited by
- 135
- References
- 51
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 7 · 2021: 15 · 2020: 7 · 2019: 11 · 2018: 8 · 2017: 13 · 2016: 10 · 2015: 15 · 2014: 7 · 2013: 9 · 2012: 6
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- MITF, melanoma, cellular senescence, DNA damage response, p53, transcription factors, growth arrest, apoptosis resistance, melanocyte lineage, cell proliferation
- MeSH terms
- Animals, DNA Damage, Humans, Melanoma, Melanoma, Experimental, Mitosis, Signal Transduction, Tumor Suppressor Protein p53, Cellular Senescence, Cell Lineage, Cell Line, Tumor, Mice, Microphthalmia-Associated Transcription Factor
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