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

基本信息

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
项目类别：
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

项目摘要

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 - 男人拥有BC的可能性是女性的3-5倍 - 站立的临床观察。即使纠正已知危害，例如吸烟和其他环境风险。目的地多年研究，卑诗省性别差异的病因，尤其是与性别作为生物变量（SABV）有关的研究，仍然不确定。我们使用由四种而不是两种性类型组成的“四核基因型”小鼠，我们确定了雌性中典型的性偏见肿瘤抑制剂：组蛋白赖氨酸脱甲基酶6a（KDM6A，又名UTX）。这 X连锁的KDM6A编码一个潜在的表观遗传调节剂，在女性中表达的高度是男性的两倍它摆脱X染色体灭活。一贯，人类KDM6A的体细胞突变，经常在两性的卑诗省患者中观察到，与女性的结局差，但男性的结局不佳。我们进一步表明X染色体既具有与性别的独立性和互动性偏见效应途径。根据已发表的初步发现，我们假设卑诗省植物的性别差异从性别染色体相关的表观遗传调节剂（即KDM6A和UTY）的影响以及性别的效果骑马（即，雄激素和雌激素），共同塑造了性别特定的表观遗传景观膀胱和性别特异性免疫肿瘤微环境。我们将以三个目的检验这一假设：1）比较男性y连锁的uty的功能与其旁系同型X连锁kdm6a，以确定是否也在体内扮演肿瘤抑制作用的角色； 2）确定KDM6A，UTY和性激素是否统称在卑诗省推动性别差异的表观遗传景观； 3）阐明KDM6A的机制差异调节了膀胱中的促肿瘤免疫微环境。长期目标该提议是两个折叠：（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和（2）将机械发现转化为BC筛查和治疗的临床改善对于男性和女性。