Regulation of androgen receptor function by H3K4 methylation in prostate cancer

H3K4 甲基化对前列腺癌中雄激素受体功能的调节

基本信息

批准号：
8518264
负责人：
Qianben Wang
金额：
$ 29.86万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518264
关键词：
Androgen Receptor Androgens Binding Biological Markers Castration Cell Proliferation Cell model Cells ChIP-seq Clinical Data Development Disease Progression Distal Enhancers Evolution Foundations Future Gene Expression Gene Targeting Genes Goals Growth Histone H3 Histones Human Lead Ligands Lysine Malignant neoplasm of prostate Mediating Messenger RNA Methylation Mitosis Modeling Molecular Oncogenes Oncogenic Ontology Outcome Pathogenesis Pathway Analysis Patients Play Process Property Regulation Resistance Role Sampling Subgroup Testing Therapeutic Tissue Microarray Tumor Suppressor Genes base castration resistant prostate cancer cdc Genes chromatin immunoprecipitation functional outcomes gain of function in vivo loss of function novel novel therapeutics promoter protein expression receptor binding receptor function therapeutic target transcription factor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Regulation of androgen receptor function by H3K4 methylation in prostate cancer Project Summary The evolution of prostate cancer from an androgen-dependent state (ADPC) to one that is castration- resistant (CRPC) marks the lethal progression of the disease. Understanding the pathogenesis of CRPC and development of novel therapies for CRPC remains an urgent need. The androgen receptor (AR), a ligand-dependent transcription factor, is still expressed and functional in CRPC; however, how AR regulates target genes in CRPC and the functional roles of AR target genes in CRPC is poorly understood. In preliminary studies we have found that AR selectively binds to enhancer regions of M- phase cell cycle genes (e.g. UBE2C) in a CRPC cell model but not in an ADPC cell model, leading to higher M-phase gene expression and faster growth of CRPC than of ADPC. Interestingly, we further found that increased histone H3 lysine 4 (H3K4) methylation level on the M-phase gene enhancers is the underlying mechanism for selective AR binding at M-phase gene enhancers in CRPC compared with ADPC. However, these studies are limited to identifying and characterizing a few enhancer H3K4 methyaltion regulated AR target genes in a pair of CRPC/ADPC cell models. In this proposal we hypothesize that enhancer and promoter H3K4 methylation directs AR in the global regulation of target genes involved in critical processes such as growth and invasion in CRPC. Our specific aims are to: (1) To determine whether the enhancer H3K4 methylation and AR play a causal role in regulating UBE2C expression and to investigate the functional role of UBE2C in various CRPC cell models and in tumorigenesis in vivo. The hypothesis that UBE2C is a direct enhancer H3K4 methylation and AR co- regulated gene that plays a critical role in growth and invasion of at least a subset of CRPC cell models and in tumorigenesis in vivo will be tested in this aim. (2) To globally identify and characterize enhancer/promoter H3K4 methylation and AR co-regulated genes in CRPC cells. The hypothesis that gain of H3K4me2 directs distal enhancer-bound AR to activate oncogenes, whereas loss of H3K4me2 and/or H3K4me3 leads to enhancer- and/or promoter-bound AR-mediated silencing of tumor suppressor genes in CRPC will be tested in this aim. (3) To examine the relevance of H3K4 methylation/AR regulation of target genes in human prostate cancer samples. The hypothesis that the data obtained from Aims 1 and 2 is relevant to human prostate cancer will be evaluated in CRPC and ADPC samples in this aim.

描述（由申请人提供）：前列腺癌项目中H3K4甲基化对雄激素受体功能的调节总结了前列腺癌从雄激素依赖性状态（ADPC）的演化到抗CRASTRATION-耐药性（CRPC）的演变，标志着该疾病的致命进展。了解CRPC的发病机理和针对CRPC的新疗法的开发仍然是迫切需要的。雄激素受体（AR）是一种依赖配体的转录因子，仍表达并在CRPC中起作用。但是，AR如何调节CRPC中的靶基因以及AR靶基因在CRPC中的功能作用知之甚少。在初步研究中，我们发现AR与CRPC细胞模型中M-相细胞周期基因（例如UBE2C）的增强剂区域有选择地结合，而在ADPC细胞模型中不选择与ADPC相比，在ADPC细胞模型中不选择更高的M相基因表达和更快的CRPC生长。有趣的是，我们进一步发现，与ADPC相比，在M期基因增强子上增加了组蛋白H3赖氨酸4（H3K4）甲基化水平，是CRPC中M相基因增强剂的选择性AR结合的基本机制。但是，这些研究仅限于识别和表征一对CRPC/ADPC细胞模型中一些增强子H3K4甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲烷的靶基因。在这项提案中，我们假设增强子和启动子H3K4甲基化指导AR在全球调节中，对参与关键过程的靶基因，例如CRPC的生长和侵袭。我们的具体目的是：（1）确定增强子H3K4甲基化和AR在调节UBE2C表达中起因果作用，并研究UBE2C在各种CRPC细胞模型和体内肿瘤发生中的功能作用。 ube2c是直接增强子H3K4甲基化和AR共同调节基因的假设，该基因在生长和侵袭至少一部分CRPC细胞模型以及体内肿瘤发生中起着至关重要的作用。（2）在CRPC细胞中，全球识别和表征增强子/启动子H3K4甲基化和AR共同调节的基因。 H3K4ME2的增益指导远端增强子结合的AR激活癌基因，而H3K4ME2和/或H3K4ME3的损失导致CRPC中CRPC中肿瘤抑制基因的增强子和/或启动子结合的AR介导的沉默。（3）检查人类前列腺癌样品中靶基因的H3K4甲基化/AR调节的相关性。在此目的中，将在CRPC和ADPC样本中评估从AIM 1和2获得的数据与人类前列腺癌相关的假设。