title: FoxO3a is an antimelanogenic factor that mediates antioxidant-induced depigmentation.
abstract: 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.
authors.affiliation: Bioscience Research Institute, R&D Center, AmorePacific Corporation, Yongin-si, Gyeonggi-do, Republic of Korea; Department of Integrated Biosciences, University of Tokyo, Chiba, Japan.
authors.forename: Juewon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Bioscience Research Institute, R&D Center, AmorePacific Corporation, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Bioscience Research Institute, R&D Center, AmorePacific Corporation, Yongin-si, Gyeonggi-do, Republic of Korea. Electronic address: egcho@amorepacific.com.
authors.forename: Eun-Gyung
authors.initials: EG
authors.lastname: Cho
authors.affiliation: Bioscience Research Institute, R&D Center, AmorePacific Corporation, Yongin-si, Gyeonggi-do, Republic of Korea. Electronic address: TRLee@amorepacific.com.
authors.forename: Tae R
authors.initials: TR
authors.lastname: Lee
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017496:Hypopigmentation / Q000235:genetics / Q000378:metabolism*; D008543:Melanins / Q000096:biosynthesis / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000502:physiology*; D008545:Melanoma; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms
chemical_list: D000975:Antioxidants; D029742:Caenorhabditis elegans Proteins; C499517:FOXO3 protein, human; C546325:FOXO3a protein, C elegans; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008543:Melanins; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases