Pathways from senescence to melanoma: focus on MITF sumoylation.

ABSTRACT

Cutaneous melanoma is a deadly skin cancer that originates from melanocytes. The development of cutaneous melanoma involves a complex interaction between environmental factors, mainly ultraviolet radiation from sunlight, and genetic alterations. Melanoma can also occur from a pre-existing nevus, a benign lesion formed from melanocytes harboring oncogenic mutations that trigger proliferative arrest and senescence entry. Senescence is a potent barrier against tumor progression. As such, the acquisition of mutations that suppress senescence and promote cell division is mandatory for cancer development. This topic appears central to melanoma development because, in humans, several somatic and germline mutations are related to the control of cellular senescence and proliferative activity. Consequently, primary melanoma can be viewed as a paradigm of senescence evasion. In support of this notion, a sumoylation-defective germline mutation in microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte homeostasis, is associated with the development of melanoma. Interestingly, this MITF variant has also been recently reported to negatively impact the program of senescence. This article reviews the genetic alterations that have been shown to be involved in melanoma and that alter the process of senescence to favor melanoma development. Then, the transcription factor MITF and its sumoylation-defective mutant are described. How sumoylation misregulation can change MITF activity and impact the process of senescence is discussed. Finally, the contribution of such information to the development of anti-malignant melanoma strategies is evaluated.