Role of MITF (Microphthalmia associated Transcription Factor) SUMOylation in skin pigmentation and nevus development. – MITF-SUMOcode

In human, skin colour is mainly due to melanins that are pigments synthesized by epidermic melanocytes. Melanin biosynthesis is a tightly regulated enzymatic process that takes place within specialized organelles called melanosomes. The transfer of melanosomes to surrounding keratinocytes allows uniform skin pigmentation and ensures an efficient photo protection against the noxious effects of the UV radiation of the solar light.
Several pathologies are associated with melanocyte dysfunctioning; vitiligo which affects 2% of the population causes severe and disfiguring depigmentation due to the loss of melanocytes; melasma and senile lentigo are hyperpigmentation diseases associated with hormonal dysfunction or ageing respectively. These pathologies are not life threatening, but may cause severe social and psychological discomfort.
Nevi are by definition benign skin lesions caused by a local benign melanocyte proliferation and aggregation. The number and the size of nevi are increased by strong and acute sun exposure. Generally speaking, nevus cells possess intermediate features between normal melanocytes and melanoma, the tumorigenic counterpart of melanocytes. Cutaneous melanoma is the 8th more frequent type of cancer in the world and affects rather young people (30-50 years old). Cutaneous melanoma is also the most rapidly increasing cancer in white population. UVA and UVB are the main etiologic factors of melanoma development. Indeed, the constant increase in melanoma frequency during the last years can be correlated to the interest of the population for sunbath and beach leisure. Noteworthy, the highest level of melanoma is found in sunny countries inhabited with fair complexion people (France 15/100000, Australia 60/100000).
Until now and despite the recent progresses in melanoma treatment, there is no efficient cure for metastatic melanoma and the best strategy remains the prevention.
MITF (MIcrophthalmia associated transcription factor) was identified as the master gene in melanocyte differentiation, which it does by controlling the expression of genes involved in all steps of melanocyte differentiation. Later on, MITF was shown to control the expression of genes involved in cell survival (BCL2, BIRC7) and in cell cycle control (CDK2). Additionally, MITF silencing blocked melanoma cell growth, indicating that MITF might favor melanoma development. However, this new dogma qualifying MITF, the first melanocyte differentiation marker, as a melanocyte lineage restricted oncogene is somehow paradoxical to an older and more universal doctrine stipulating that tumour differentiation is inversely correlated with its aggressiveness. Therefore, consideration should be given to a dual functionality of MITF that might be controlled by post-translational modifications such as SUMOylations. Although, these modifications have been reported and studied in vitro, their functional consequences in vivo had never been elucidated.
Very recently, we have demonstrated that the alteration of MITF SUMOylation may favor melanoma development. Indeed, we identified a new MITF germline mutation (MITF E318K) that impairs severely MITF SUMOylation and predisposes carriers to develop melanoma and kidney cancer. This variant allele was also associated with increased naevus number, black eye colour and fair complexion skin.
Therefore, our project will focus on the study of MITF SUMOylation in melanocyte physiological or pathological functioning. Using both in vitro (cultured cells) and in vivo (mouse models) approaches, we will study the role of MITF SUMOylation in melanocyte growth and differentiation as well as in the development of pre-malignant lesions that are the nevi.