Protooncogene MYC drives human melanocyte melanogenesis and senescence.

In spite of extensive research and advances on the molecular biology of melanoma, the process of melanocytic differentiation or its relationship with proliferation is poorly understood. The role of proto-oncogenes in normal melanocyte biology is also intriguing. Proto-oncogene MYC is overexpressed in 40% of melanomas. It has been suggested that MYC can mediate senescence bypass in malignant melanocytes, an important event in melanoma development, likely in cooperation with other oncogenic pathways. However, despite the apparent importance of MYC in melanoma, its functions in normal melanocytes are unknown. We have overexpressed MYC in freshly isolated human primary melanocytes and studied the effects on melanocytic proliferation and differentiation. MYC promoted a transient activation of melanocytes including cell cycle entry, DNA damage and cell migration. Subsequently, MYC induced melanogenesis, increased cellular size and complexity and senescence. Interestingly, we also found strong expression of MYC in regions of human nevi displaying high pigmentation and high expression of senescence marker p16. The results altogether show that MYC drives melanocytic differentiation and suggest that senescence is associated with differentiation. We discuss the implications into the mechanisms governing melanocytic differentiation and the development of melanoma.