Sex-biasedYap1oncogene function

Abstract

ABSTRACTThe incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogeneYap1is sexually dimorphic in medulloblastoma progression and immune suppression. We show thatYap1promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions ofSox2, Atoh1, NeuroD1, and Zic1/2. Yap1also promotes an immune suppressive tumor microenvironment by directly regulatingCsf1, Igf1,andIgfbp3transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably,Yap1function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1.