Bladder cancer (BCa) exhibits a striking sex bias: men are 3-5 times more likely than women to develop and die from BCa. Even when known risk factors such as smoking, infection, occupational hazards, cultural and environmental factors are corrected for, this phenomenon persists. Despite this long-standing clinical observation, men and women still receive relatively similar treatments due to a lack of mechanistic understanding to derive useful treatments based on biological sex. In this proposal, we seek to elucidate the mechanistic basis of sexual dimorphism in tumor biology. It is well established that gonadal hormone effects (GHE), defined by gonad- derived hormonal factors that drive sex disparities in BCa, are primarily mediated by male dominant androgens and androgen receptor (AR). Recently, we reported an unexpected sex chromosome effect (SCE) that independently contributes to the sexual dimorphism of BCa; we found that SCE is predominantly mediated by lysine (K) demethylase 6a (KDM6A), which functions as a female-biased tumor suppressor gene in the bladder. KDM6A demethylase is a versatile epigenetic regulator that controls histone methylations in both enzymatic activity development and independent mechanisms. We will refer the sex-specific epigenome to as the sex epigenome. We hypothesize that the sex epigenome, programed by KDM6A directly and AR indirectly, controls sexual dimorphism in gene expression and BCa. We designed three specific aims to test this hypothesis: 1) to determine whether KDM6A shapes directly the sex epigenome and regulates the local bioavailability of sex hormones in the bladder; 2) to determine whether AR opposes the KDM6A-dependent sex epigenome in the bladder; and 3) to determine whether the sex epigenome differentially regulates genes during bladder carcinogenesis. Success of the proposal will catalyze the identification of sex-biased genes and regulatory elements for the design of sex-specific BCa screening and treatment. Results from our proposed studies will also advance the mechanistic understanding behind greater BCa incidence in males and lead future efforts to prevent and treat BCa according to a patient's biological sex. Because male dominance in cancer incidence and mortality is observed across most non-reproductive cancer types, an improved understanding of sexual dimorphism in BCa will also have widespread implications on these cancers.