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--项目总结 膀胱癌(BC)的性别差异--男性患膀胱癌的可能性是女性的3-5倍--是一个很长的问题 长期临床观察。这种差距在社会经济和地理阶层中持续存在，即使在 纠正已知的危害，如吸烟和其他环境风险。然而，尽管多年来 研究，卑诗省性别差异的病因学，特别是当它与性别作为生物变量(SABV)有关时， 仍然没有明确的定义。使用由四种性别类型而不是两种性别组成的“四核心基因型”小鼠，我们确定了 一种典型的女性性别偏见肿瘤抑制因子：组蛋白赖氨酸去甲基酶6A(KDM6A，又名UTX)。这个 X连锁KDM6A编码一种有效的表观遗传调节因子，在雌性体内的表达水平是雄性的两倍 从X染色体失活中逃脱。一贯，人类KDM6A的体细胞突变频繁 在BC患者中观察到的，无论性别，与女性预后不良有关，但与男性无关。我们进一步 表明X染色体与性激素既有独立的性别偏向效应，也有相互作用的性别偏向效应 小路。根据已发表的和初步的发现，我们假设BC茎的性别差异 从性染色体连锁的表观遗传调节子(即KDM6A和UTY)的影响和性别的影响 激素(即雄激素和雌激素)，共同塑造了性别特异的表观遗传格局 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一假设：1) 比较Y连锁UTY与其类X连锁KDM6A在男性中的功能，以确定UTY是否也 在体内发挥肿瘤抑制作用；2)确定KDM6A、UTY和性激素是否共同形成 表观遗传格局驱动BC性别差异；3)阐明KDM6A 不同地调节膀胱内促肿瘤免疫微环境。的长期目标 这一建议有两个方面：(1)确定调节特定性别膀胱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进 无论是男性还是女性。