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

• 批准号: 8895857
• 负责人: Qianben Wang
• 金额: $ 31.77万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895857
• 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; Massive Parallel Sequencing; 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

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）：前列腺癌中H3 K4甲基化对雄激素受体功能的调节前列腺癌从雄激素依赖性状态（ADPC）到去势抵抗性状态（CRPC）的演变标志着该疾病的致死性进展。了解CRPC的发病机制和开发CRPC的新疗法仍然是迫切需要的。雄激素受体（AR）是一种配体依赖性转录因子，在CRPC中仍有表达和功能;然而，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选择性结合CRPC细胞模型中M期细胞周期基因（例如UBE 2C）的增强子区域，但不结合ADPC细胞模型中的增强子区域，导致CRPC的M期基因表达高于ADPC，并且CRPC的生长更快。有趣的是，我们进一步发现，与ADPC相比，CRPC中M期基因增强子上组蛋白H3赖氨酸4（H3 K4）甲基化水平的增加是M期基因增强子选择性AR结合的潜在机制。然而，这些研究仅限于在一对CRPC/ADPC细胞模型中鉴定和表征少数增强子H3 K4甲基化调节的AR靶基因。在这个提议中，我们假设增强子和启动子H3 K4甲基化指导AR在CRPC中参与关键过程如生长和侵袭的靶基因的全局调节。我们的具体目标是：（1）确定增强子H3 K4甲基化和AR是否在调节UBE 2C表达中起因果作用，并研究UBE 2C在各种CRPC细胞模型和体内肿瘤发生中的功能作用。在此目的中，将测试UBE 2C是直接增强子H3 K4甲基化和AR共调节基因的假设，其在CRPC细胞模型的至少一个子集的生长和侵袭中以及在体内肿瘤发生中起关键作用。(2)全面鉴定和表征CRPC细胞中增强子/启动子H3 K4甲基化和AR共调节基因。在CRPC中，H3 K4 me 2的获得指导远端增强子结合的AR激活癌基因，而H3 K4 me 2和/或H3 K4 me 3的缺失导致增强子和/或启动子结合的AR介导的肿瘤抑制基因沉默的假设将在此目的中进行测试。(3)研究人前列腺癌样本中靶基因H3 K4甲基化/AR调控的相关性。将在CRPC和ADPC样本中评价从目的1和2获得的数据与人前列腺癌相关的假设。