Sexual Dimorphism in Bladder Cancer

膀胱癌(BCA)表现出明显的性别偏见：男性发生和死亡的可能性是女性的3-5倍 来自BCA的。即使已知的危险因素，如吸烟、感染、职业危害、文化和 环境因素被修正后，这一现象依然存在。尽管有这种长期的临床观察， 由于缺乏机制上的理解，男性和女性仍然接受相对相似的治疗 基于生物性的有用的治疗方法。在这个提议中，我们试图阐明性行为的机制基础。 肿瘤生物学中的二形性。众所周知，性腺激素效应(GHE)，由性腺- 导致BCA性别差异的衍生激素因素主要是由男性主导的雄激素介导的 和雄激素受体(AR)。最近，我们报道了一种意想不到的性染色体效应 独立导致BCA的性别二型性；我们发现姐妹染色单体交换主要是由 赖氨酸(K)去甲基酶6a(KDM6A)，其功能是在膀胱中作为女性偏向的肿瘤抑制基因。 KDM6A去甲基酶是一种多功能的表观遗传调节因子，它控制着两种酶中的组蛋白甲基化 活动发展和独立机制。我们将性别特定的表观基因组称为性别 表观基因组。我们假设由KDM6A直接编程和AR间接编程的性表观基因组控制 基因表达和BCA的性别二型性。我们设计了三个具体目标来检验这一假设：1) 确定KDM6A是否直接形成性表观基因组并调节性的局部生物利用度 膀胱中的激素；2)确定AR是否反对KDM6A依赖的性表观基因组 膀胱；以及3)确定性表观基因组是否在膀胱期间对基因进行差异调控 致癌。该提案的成功将促进性别偏见基因的识别和监管 针对性别的BCA筛查和治疗的设计要素。我们建议的研究结果将 也促进了对男性BCA发病率更高背后的机制的理解，并领导未来的努力 根据患者的生物性别预防和治疗BCA。因为男性在癌症发病率和 死亡率在大多数非生殖性癌症类型中被观察到，这是对性行为的更好的理解 BCA的二型性也将对这些癌症产生广泛的影响。

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.