title: The DNA methylation inhibitor 5-azacytidine decreases melanin synthesis by inhibiting CREB phosphorylation.
abstract: Here we examined the effects of a DNA methylation inhibitor, 5-azacytidine, on melanogenesis in Mel-Ab cells. We found that 5-azacytidine decreased the melanin content and tyrosinase activity in these cells in a dose-dependent manner; importantly, 5-azacytidine was not cytotoxic at the concentrations used in these experiments. On the other hand, 5-azacytidine did not affect tyrosinase activity in a cell-free system, indicating that 5-azacytidine is not a direct tyrosinase inhibitor. Instead, 5-azacytidine decreased the protein levels of microphthalmia-associated transcription factor (MITF) and tyrosinase. Thus, we investigated the effects of 5-azacytidine on signal transduction pathways related to melanogenesis. However, 5-azacytidine did not have any effect on either Akt or glycogen synthase kinase 3β (GSK3β) phosphorylation. The phosphorylation of cAMP response element-binding protein (CREB) is well known to regulate MITF expression, thereby also regulating tyrosinase expression. We found that 5-azacytidine decreased the phosphorylation of CREB. Therefore, we propose that 5-azacytidine may decrease melanin synthesis by downregulating MITF and tyrosinase via CREB inactivation.
authors.forename: Jun Seob
authors.initials: JS
authors.lastname: Shin
authors.forename: Hyo-Soon
authors.initials: HS
authors.lastname: Jeong
authors.forename: Myo-Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Yun
authors.forename: Kwang Jin
authors.initials: KJ
authors.lastname: Baek
authors.forename: Nyoun Soo
authors.initials: NS
authors.lastname: Kwon
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Kim
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D017362:Cyclic AMP Response Element-Binding Protein; D008543:Melanins; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; D001374:Azacitidine