The Kdm6a-dependent Sex Epigenome in Bladder Tumor Suppression

Kdm6a 依赖性性别表观基因组在膀胱肿瘤抑制中的作用

• 批准号: 10629080
• 负责人: Xue Sean Li
• 金额: $ 54.11万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629080
• 关键词: 3-Dimensional; Affect; Androgen Receptor; Androgens; Automobile Driving; Biological; Bladder; Bladder Neoplasm; Bladder Urothelial Cell; Breast Cancer Cell; CCL8 gene; Cancer Patient; Chromosomes; Clinical; Data; Development; Differentiation and Growth; Disease; Disparity; Environmental Risk Factor; Epigenetic Process; Estrogen Receptors; Estrogens; Etiology; Exhibits; Female; Four Core Genotypes; Future; Gene Expression Regulation; Gene Proteins; Genes; Genetic Transcription; Geography; Gonadal Steroid Hormones; Growth; Histones; Human; Immune; Immunity; Incidence; Interferon alpha; Knockout Mice; Knowledge; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Monocyte Chemoattractant Proteins; Mus; Natural regeneration; Odds Ratio; Organoids; Outcome; Pathway interactions; Patients; Play; Publishing; Regulation; Reporting; Research; Risk Factors; Role; Screening for cancer; Sex Bias; Sex Chromosomes; Sex Differences; Shapes; Smoking; Somatic Mutation; TP53 gene; Testing; Tissues; Translating; Transplantation; Tumor Suppression; Tumor Suppressor Proteins; Urinary tract infection; Urothelium; Woman; X Chromosome; X Inactivation; cancer cell; cancer initiation; cancer risk; chemokine; chromosome Y loss; conditional knockout; epigenome; genome-wide analysis; hazard; immunoregulation; improved; in vivo; knock-down; male; men; mortality; muscle invasive bladder cancer; mutant; neutralizing antibody; non-muscle invasive bladder cancer; novel therapeutics; paralogous gene; prostate cancer cell; response; sex; sex disparity; sexual dimorphism; socioeconomics; stem; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

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.

项目 3 – 项目摘要 膀胱癌 (BC) 的性别差异——男性患 BC 的可能性是女性的 3-5 倍——是一个长期存在的问题。 站立临床观察。即使在不同社会经济和地理阶层之间，这种差异仍然存在 纠正已知的危害，例如吸烟和其他环境风险。然而尽管多年 研究，BC 性别差异的病因学，特别是与性别作为生物变量 (SABV) 相关， 仍然不明确。使用由四种而不是两种性别类型组成的“四核基因型”小鼠，我们发现 女性中典型的性别偏见肿瘤抑制因子：组蛋白赖氨酸脱甲基酶 6A（KDM6A，又名 UTX）。这 X连锁KDM6A编码一种有效的表观遗传调节因子，其在女性中的表达量是男性的两倍，因为 使其逃脱 X 染色体失活。一致地，人类 KDM6A 的体细胞突变经常发生 在两种性别的 BC 患者中观察到的结果与女性的不良预后相关，但与男性的不良预后无关。我们进一步 表明X染色体与性激素既具有独立的性别偏向作用，又具有相互作用的性别偏向作用 途径。根据已发表的初步研究结果，我们假设 BC 的性别差异源于 来自性染色体连锁表观遗传调节因子（即 KDM6A 和 UTY）的影响以及性别的影响 激素（即雄激素和雌激素）共同塑造了性别特异性的表观遗传景观 膀胱和性别特异性免疫肿瘤微环境。我们将通过三个目标来检验这个假设：1) 比较男性中 Y 连锁 UTY 与其旁系同源 X 连锁 KDM6A 的功能，以确定 UTY 是否也 在体内发挥抑癌作用； 2) 确定KDM6A、UTY和性激素是否共同塑造 BC省性别差异的表观遗传景观； 3）阐明KDM6A的作用机制 差异调节膀胱中的促肿瘤免疫微环境。的长期目标 该提议有两个方面：（1）确定调节性别特异性膀胱的关键表观遗传和免疫途径 肿瘤发生以及 (2) 将机制发现转化为 BC 筛查和治疗的临床改进 适合男性和女性。