GPR87 promotes DMBA/TPA-induced skin tumorigenesis through the YAP-SOX2 axis.

G protein-coupled receptor 87 (GPR87) has been implicated in the growth and progression of several malignancies, but its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Here, we found that GPR87 was aberrantly upregulated in murine and human skin tumors and in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated HaCaT keratinocytes. Using a 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced mouse skin tumor model, we demonstrated that GPR87 knockout significantly delayed epidermal hyperplasia, tumor initiation, and malignant progression. Consistently, GPR87 knockdown suppresses TPA-induced keratinocyte proliferation, migration, stemness, and epithelial-mesenchymal transition in keratinocytes and cSCC cells. Mechanistically, GPR87 deficiency markedly reduced SOX2 expression in cultured cells and skin lesions. GPR87 knockdown also enhanced mammalian STE20-like serine/threonine kinases 1/2 (MST1/2) and large tumor suppressor kinases (LATS1/2) phosphorylation, increased inhibitory YAP phosphorylation, and suppressed Yes-associated protein (YAP) nuclear localization and downstream transcriptional activity. Importantly, activation of YAP by either YAP(S127A) expression or XMU-MP-1 treatment restored SOX2 expression in GPR87-depleted cells, whereas verteporfin-mediated inhibition of YAP-TEA domain transcription factor (TEAD) activity attenuated TPA-induced SOX2 upregulation. Together, these findings identify GPR87 as a key positive regulator of skin tumor initiation and progression and demonstrate that its tumor-promoting effects are mediated, at least in part, through the YAP-SOX2 axis. GPR87 may therefore represent a potential therapeutic target for cSCC.