The Kdm6a-dependent Sex Epigenome in Bladder Tumor Suppression

项目3 -项目概要 膀胱癌（BC）的性别差异-男性患BC的可能性是女性的3-5倍-是一个长期的- 长期临床观察这种差异在社会经济和地理阶层中持续存在， 纠正已知的危害，如吸烟和其他环境风险。尽管多年来 研究，BC性别差异的病因，特别是因为它涉及到性别作为一个生物变量（SABV）， 仍然不明确。使用由四种而不是两种性别类型组成的“四核心基因型”小鼠，我们发现， 一种典型的女性性别偏向性肿瘤抑制因子：组蛋白赖氨酸脱甲基酶6A（KDM 6A，又名UTX）。的 X连锁KDM 6A编码一种有效的表观遗传调节因子，其在女性中的表达是男性的两倍， 从X染色体失活中逃脱一致的是，人KDM 6A的体细胞突变，经常 在两种性别的BC患者中观察到，与女性的不良结局相关，但与男性无关。我们进一步 表明X染色体既有独立的性别偏向作用，又有与性激素相互作用的性别偏向作用 途径。基于已发表的和初步的研究结果，我们假设BC的性别差异源于 来自性染色体连锁的表观遗传调节因子的影响（即，KDM 6A和UTY）和性别的影响 激素（即，雄激素和雌激素），共同塑造了一个性别特异性表观遗传景观， 膀胱和性特异性免疫肿瘤微环境。我们将以三个目标来检验这一假设：1） 比较Y-连锁UTY在男性中的功能与其配偶X-连锁KDM 6A，以确定UTY是否也 在体内起肿瘤抑制作用; 2）确定KDM 6A、UTY和性激素是否共同形成 表观遗传景观，以推动性别差异在公元前; 3）阐明机制，通过KDM 6A 差异调节膀胱中的促肿瘤发生免疫微环境。的长期目标 该建议有两个方面：（1）确定调节性别特异性膀胱炎的关键表观遗传和免疫途径 肿瘤发生和（2）将机制发现转化为BC筛查和治疗的临床改善 对于男性和女性。

PROJECT 3 – PROJECT SUMMARY Sex differences in bladder cancer (BC)—men being 3-5 times more likely to have BC than women—are a long- standing clinical observation. Such disparities persist across socioeconomic and geographic strata even when correcting for known hazards such as smoking and other environmental risks. Yet despite many years of research, the etiology of BC sex differences, especially as it relates to sex as a biological variable (SABV), remains ill-defined. Using “four-core genotypes” mice that consist of four instead of two sex types, we identified a prototypical sex-biasing tumor suppressor in females: histone lysine demethylase 6A (KDM6A, aka UTX). The X-linked KDM6A encodes a potent epigenetic regulator that expresses twice as high in females as in males due to its escape from X-chromosome inactivation. Consistently, somatic mutations of human KDM6A, frequently observed in BC patients of both sexes, are correlated with poor outcomes in females but not in males. We further showed that the X chromosome has both an independent and interactive sex-biasing effects with sex hormone pathways. Based on the published and preliminary findings, we hypothesize that sex differences in BC stems from effects of the sex chromosome linked epigenetic regulators (i.e., KDM6A and UTY) and effects of the sex hormones (i.e., androgens and estrogens), collectively shaping a sex specific epigenetic landscape in the bladder and sex specific immune tumor microenvironment. We will test this hypothesis with three aims: 1) compare the function of Y-linked UTY in males with its paralog X-linked KDM6A to determine whether UTY also plays a tumor suppressor role in vivo; 2) determine whether KDM6A, UTY, and sex hormones collectively shape the epigenetic landscape to drive sex differences in BC; 3) elucidate the mechanism through which KDM6A differentially modulates pro-tumorigenic immune microenvironment in the bladder. The long-term objectives of this proposal are two-fold: (1) identify key epigenetic and immune pathways that modulate sex-specific bladder tumorigenesis and (2) translate mechanistic discoveries to clinical improvement in BC screening and treatment for males and females.