P2RY6 is highly expressed in skin keratinocytes, but its function in
skin diseases is unclear. We use a two-step chemical induction method to induce mouse skin
tumor formation. Multiple in vitro and in vivo assays were used to explore the role of P2RY6 in skin
tumors. We report that P2ry6-deficient mice exhibit marked resistance to 7,12-dimethylbenz[a]
anthracene/12-O-tetradecanoylphorbol-13-
acetate (TPA)-induced skin
papilloma formation compared with wild-type mice. Consistent with these findings, epidermal
hyperplasia in response to TPA was suppressed in the P2ry6-knockout or
MRS2578 (P2RY6 antagonist)-treated mice. The dramatic decrease in
hyperplasia and
tumorigenesis due to P2ry6 disruption was associated with the suppression of TPA-induced keratinocyte proliferation and inflammatory reactions. Notably, P2ry6 deletion prevented the TPA-induced increase in YAP nuclear accumulation and its downstream gene expression in an MST/LATS1-dependent manner. On TPA stimulation, enhanced activation of MAPK/extracellular signal‒regulated
kinase kinase 1 and β-
catenin were also impaired in P2ry6-knockout primary keratinocytes,
tumor tissues, or MRS2578-treated HaCaT cells. Moreover, mutual promotion of the YAP and β-
catenin signaling pathways was observed in normal skin cells treated with TPA, whereas P2ry6 deletion could inhibit their crosstalk by regulating MAPK/extracellular signal‒regulated
kinase kinase 1. Thus, P2RY6 is a critical positive regulator of skin
tumorigenesis through the modulation of the Hippo/YAP and Wnt/β-
catenin signaling pathways.