G protein-coupled estrogen receptor enhances melanogenesis via cAMP-protein kinase (PKA) by upregulating microphthalmia-related transcription factor-tyrosinase in melanoma

•Agonist and antagonist treatment altered GPER activation in A375 and B16 cells.•GPER upregulation upregulated TYR and MITF expression and TYR activity.•GPER upregulation promoted cell proliferation and melanogenesis in A375 cells.•GPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling.•GPER is a potential drug target for chloasma treatment.

ObjectiveThis study investigated the role and mechanism of action of G protein-coupled estrogen receptor (GPER) in melanogenesis.MethodsGPER expression was detected in the A375 human melanoma cell line and B16 mouse melanoma cell line. Cell proliferation, melanin content, tyrosinase (TYR) activity, cyclic adenosine monophosphate (cAMP) level, and TYR and microphthalmia-related transcription factor (MITF) expression were measured. GPER activation was altered by agonist and antagonist treatment and its expression was downregulated by gene silencing. Estradiol-induced melanin synthesis and the activation of related signaling pathways were suppressed by inhibiting GPER via antagonist treatment. The relationship between GPER and TYR was evaluated in clinical chloasma samples by immunohistochemistry.ResultsUpregulation of GPER in A375 cells promoted melanogenesis, favored as indicated by increases in TYR and MITF expression and TYR activity. GPER activated melanin production via the cAMP-protein kinase (PK) A pathway, suggesting that GPER plays an important role in estrogen-induced melanin synthesis. The effect of GPER activation on cAMP-MITF-TYR signaling was also demonstrated in B16 cells. A significant association was observed between GPER and TYR expression in chloasma skin lesions relative to normal skin.ConclusionGPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling and modulates the effects of estrogen in melanogenesis. GPER is therefore a potential drug target for chloasma treatment.