Sexual Dimorphism in Bladder Cancer

膀胱癌的性别二态性

• 批准号: 10522918
• 负责人: Xue Sean Li
• 金额: $ 57.72万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522918
• 关键词: Address; Affect; Androgen Receptor; Bacterial Artificial Chromosomes; Biological; Biological Availability; Biology; Bladder; Bladder Neoplasm; Chemicals; Chromatin; Clinical; Data; Development; Disease; Down-Regulation; Environmental Risk Factor; Epigenetic Process; Exhibits; Female; Four Core Genotypes; Future; Gene Expression; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genitourinary system; Glucuronosyltransferase; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Histones; Hormonal; Human; Incidence; Infection; Investigation; Knockout Mice; Lead; Libido; Light; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Modeling; Mus; Mutation; Oncogenes; Outcome; Ovary; Pathway interactions; Patients; Physiological; Regulation; Regulatory Element; Reporting; Risk Factors; Role; Screening for cancer; Sex Bias; Sex Chromosomes; Sex Differences; Shapes; Smoking; System; Technology; Testing; Testis; Time; Transgenic Mice; Tumor Biology; Tumor Suppressor Genes; Tumor Suppressor Proteins; UGT1A1 gene; Uridine; Urothelium; Woman; X Chromosome; XX male; XY females; base; biological sex; cancer type; carcinogenesis; conditional knockout; design; epigenome; gain of function; histone methylation; improved; in vivo; male; men; mortality; mutant; novel; occupational hazard; prevent; programs; sex; sex disparity; sexual dimorphism; success; transcription factor; transcriptome; tumor; tumorigenesis

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.

膀胱癌（BCa）表现出惊人的性别偏见：男性比女性更容易发展和死亡3-5倍 在BCa。即使已知的风险因素，如吸烟，感染，职业危害，文化和 尽管环境因素得到了纠正，但这种现象仍然存在。尽管这种长期的临床观察， 男性和女性仍然接受相对相似的治疗，因为缺乏对获得 基于生物性别的有用治疗方法。在这个建议中，我们试图阐明性的机械基础， 肿瘤生物学中的二态性。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由男性显性雄激素介导 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（SCE）， BCa的性别二型性独立贡献;我们发现SCE主要由 赖氨酸（K）脱甲基酶6a（KDM 6A），其在膀胱中作为女性偏好的肿瘤抑制基因起作用。 KDM 6A脱甲基酶是一种多功能的表观遗传调节因子，在两种酶促反应中控制组蛋白甲基化。 活动发展和独立机制。我们将性别特异性表观基因组称为性别 表观基因组。我们假设，由KDM 6A直接和AR间接编程的性表观基因组控制了 基因表达和BCa的两性异形。我们设计了三个具体目标来验证这一假设：1） 确定KDM 6A是否直接塑造性表观基因组并调节性的局部生物利用度 2）确定AR是否对抗膀胱中依赖KDM 6A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发育过程中差异调节基因。 致癌作用该提案的成功将促进性别偏见基因和调控基因的识别。 设计性别特异性BCa筛查和治疗的要素。我们的研究结果将 还促进了对男性BCa发病率更高背后的机制的理解，并引导未来的努力， 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 在大多数非生殖性癌症类型中观察到死亡率， BCa的二型性也将对这些癌症产生广泛的影响。