Forkhead box-O (FoxO) family transcriptional factors control the expression of many genes involved in a variety of cellular processes. Melanogenesis is an oxidizing process; therefore, many antioxidants are used to inhibit melanin production. However, their mechanism of action is poorly understood. In this study, we investigated the role of FoxO3a, which is a key factor in oxidative stress-related cellular responses in melanogenesis. When FoxO3a expression was inhibited, the expression of melanogenic genes and melanin levels increased. In contrast, the overexpression of wild-type FoxO3a and the increased nuclear translocation induced by the phosphoinositide 3-kinase inhibitors or by Akt inhibition reversed these phenomena. This effect was not observed when FoxO3a harbored a deletion in the nuclear localization signal, indicating that its nuclear translocation is important for the regulation of melanogenesis. When antioxidants such as vitamin C, N-acetylcysteine, and Trolox were applied to MNT1 cells, melanin levels decreased in parallel with FoxO3a nuclear translocation, and this effect disappeared with FoxO3a-directed small interfering RNA treatment. Because FoxO3a orchestrates the expression of many genes in order to regulate cellular phenotypes in a variety of environmental states, this gene, a factor involved in melanogenesis regulation, may represent a good target for studying antimelanogenic signaling pathways and for designing pharmacological or antimelanogenic agents that regulate melanin synthesis.
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