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Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma

Abstract

Malignant melanoma is an aggressive cancer known for its notorious resistance to most current therapies. The basic helix-loop-helix microphthalmia transcription factor (MITF) is the master regulator determining the identity and properties of the melanocyte lineage, and is regarded as a lineage-specific ‘oncogene’ that has a critical role in the pathogenesis of melanoma. MITF promotes melanoma cell proliferation, whereas sustained supression of MITF expression leads to senescence. By combining chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) and RNA sequencing analyses, we show that MITF directly regulates a set of genes required for DNA replication, repair and mitosis. Our results reveal how loss of MITF regulates mitotic fidelity, and through defective replication and repair induces DNA damage, ultimately ending in cellular senescence. These findings reveal a lineage-specific control of DNA replication and mitosis by MITF, providing new avenues for therapeutic intervention in melanoma. The identification of MITF-binding sites and gene-regulatory networks establish a framework for understanding oncogenic basic helix-loop-helix factors such as N-myc or TFE3 in other cancers.

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Acknowledgements

We thank B Jost for Illumina sequencing, A Hamiche and E Soutoglou for antibodies. This work was supported by grants from the CNRS, the INSERM, the Association pour la Recherche contre le Cancer grant 4985 and 7823, the Ligue Nationale contre le Cancer, the Institut national du Cancer grant R08009AP and the ANR Regulome project grant. We thank the Conseil Regional de la Région Provence-Alpes-Cote d’Azur, the Nice University Hospital and the Conseil Général des Alpes Maritimes for funding of the C3M MiCa Cell Imaging Facility. ID and CB are ‘équipes labellisées’ of the Ligue Nationale contre le Cancer.

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Correspondence to C Bertolotto or I Davidson.

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Strub, T., Giuliano, S., Ye, T. et al. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Oncogene 30, 2319–2332 (2011). https://doi.org/10.1038/onc.2010.612

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