Régulation épigénétique de l’expression génique dans le mélanome malin

Abstract

Malignant melanoma is a highly aggressive cancer with a propensity for early metastasis. Melanocyte transformation results predominantly from oncogenic mutations in BRAF, NRAS or NF1 leading to constitutive activation of the MAP kinase pathway driving cell proliferation and second site mutations such as loss of CDKN1A, or PTEN or activating mutations in the beta-catenin pathway that allow escape from oncogene induced senescence. Nevertheless, irrespective of the nature of the driver mutations, melanoma cell physiology is strongly regulated by transcription factors and epigenetic mechanisms. MITF (Microphthalmia-associated Transcription Factor) and SOX10 are two major transcription factors that regulate both normal melanocyte and melanoma cell physiology. Using a combination of mouse genetics, biochemistry and high throughput genomics we have identified cofactors for MITF and addressed the mechanisms by which MITF, SOX10 and their cofactors regulate gene expression in melanocytes and melanoma.