FoxO6 inhibits melanogenesis partly by elevating intracellular antioxidant capacity

Of the various transcription factors that play a role in controlling oxidative stress, the role of FoxO proteins in skin aging has recently become of interest. Unlike other FoxOs, FoxO6 remains in the nucleus due to the lack of nuclear export signal, so that it may respond sensitively to intracellular stimuli for the induction of target genes. However, the role of FoxO6 in melanogenesis and its related signaling pathways are unclear. We used UV exposed and intrinsically aged mice that exhibited skin aging. Our data showed that FoxO6 activation was markedly decreased in the skin of aging mice and UVB-exposed hairless mice that exhibited an increase in melanogenesis. The reduced FoxO6 activity was closely associated with the elevation of oxidative stress in the skin of these animal models. To our interest, siRNA-mediated FoxO6 knockdown markedly increased melanin content and related signaling pathways in B16F10 cells even without any stimulation. On the contrary, adenovirus-mediated FoxO6 activation significantly reduced melanin content in UVB-exposed B16F10 cells, which is closely associated with the induction of antioxidant genes including MnSOD and catalase, leading to a decrease in oxidative stress. Furthermore, vitamin C treatment reversed the elevated melanogenesis by the FoxO6 knockdown, indicating that the decreased antioxidant capacity greatly contributes to increased melanogenesis in the FoxO6 knockdown condition. For the upstream of a FoxO6 signaling pathway in melanocytes, FoxO6 phosphorylation by Akt appears to be essential evidenced by the reduction of FoxO6 activity and the increase in melanogenesis by PI3K/AKT inhibitor treatment. Our study suggests that FoxO6 is an antioxidant gene that prevents oxidative stress-induced melanogenesis.