Melanopsin mediates UVA-dependent modulation of proliferation, pigmentation, apoptosis, and molecular clock in normal and malignant melanocytes

Cutaneous melanocytes and melanoma cells express several opsins, of which melanopsin (OPN4) detects temperature and UVA radiation. To evaluate the interaction between OPN4 and UVA radiation, normal and malignant Opn4^WT and Opn4^KO melanocytes were exposed to three daily low doses (total 13.2 kJ/m²) of UVA radiation. UVA radiation led to a reduction of proliferation in both Opn4^WT cell lines; however, only in melanoma cells this effect was associated with increased cell death by apoptosis. Daily UVA stimuli induced persistent pigment darkening (PPD) in both Opn4^WT cell lines. Upon Opn4 knockout, all UVA-induced effects were lost in three independent clones of Opn4^KO melanocytes and melanoma cells. Per1 bioluminescence was reduced after 1st and 2^nd UVA radiations in Opn4^WT cells. In Opn4^KO melanocytes and melanoma cells, an acute increase of Per1 expression was seen immediately after each stimulus. We also found that OPN4 expression is downregulated in human melanoma compared to normal skin, and it decreases with disease progression. Interestingly, metastatic melanomas with low expression of OPN4 present increased expression of BMAL1 and longer overall survival. Collectively, our findings reinforce the functionality of the photosensitive system of melanocytes that may subsidize advancements in the understanding of skin related diseases, including cancer.