Role of NF90 in Prostate Cancer

NF90 在前列腺癌中的作用

基本信息

批准号：
9754800
负责人：
Jindan Yu
金额：
$ 35.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754800
关键词：
Affinity Chromatography American Androgen Receptor Androgens Apoptosis Binding Biological Assay Cancer Etiology Cancer Patient Castration Cell Cycle Cell division Cessation of life ChIP-seq Chromatin Clinical Clinical Trials Complex Data Development Diagnosis Double-Stranded RNA EZH2 gene Enhancers Epigenetic Process Event Exhibits Gene Activation Gene Expression Genes Genetic Transcription Goals Growth Histone H3 Hyperactive behavior In Vitro Light Lysine Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Metastatic Prostate Cancer Methylation Molecular Mutation Neoplasm Metastasis Oncogenes Oncogenic Operative Surgical Procedures Outcome Pathway interactions Patients Play Polycomb Prognostic Marker Proteins Radiation therapy Receptor Activation Regulation Research Resistance Resistance development Role SET Domain Sampling Testing Therapeutic Therapeutic Intervention Tissues Transcription Coactivator Transcriptional Activation Tumor Suppressor Genes Work Xenograft Model androgen deprivation therapy castration resistant prostate cancer clinically relevant combinatorial efficacy testing genome-wide histone methyltransferase in vivo inhibitor/antagonist knock-down men mutant new therapeutic target novel nuclear factor of activated T-cells, 90 kD overexpression preclinical study promoter prostate cancer cell prostate carcinogenesis receptor expression recruit targeted treatment therapeutic target transcriptome sequencing tumor tumor growth

项目摘要

Summary Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer and the third leading cause of cancer deaths in American men. While early-stage PCa can be effectively treated with surgery and radiation therapy, metastatic prostate cancer remains a challenge and androgen deprivation therapy (ADT) is the mainstay treatment. Although a majority of advanced PCa initially responds well to ADT, they ultimately develop resistance and become castration- resistant, called CRPC. CRPC tumors no longer need androgen to grow but often remain dependent on an aberrantly active androgen receptor (AR). Understanding the mechanisms to this androgen-independent AR activation may shed significant light on effective strategies to eradicate CRPC. EZH2 is an enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2) that catalyzes histone H3 lysine 27 trimethylation to suppress gene expression, a role that can be effectively targeted by enzymatic EZH2 inhibitors. Recent evidence suggests that EZH2 may have PRC2-independent roles in activating gene expression. However, critical gaps remain as to what the target genes are, how EZH2 activates them, and how they work in concert with the epigenetic roles of EZH2 to promote CRPC. Our preliminary results showed that AR is a direct target of EZH2-mediated transcriptional activation. This activation is likely mediated by EZH2- interacting co-activator NF90. Our preliminary data further showed that NF90 is up-regulated in CRPC and exhibits oncogenic functions. The roles of NF90, however, have never been studied in PCa. We hypothesize that NF90 cooperates with EZH2 in transcriptional activation of AR and promotes CRPC progression. To test these hypotheses, three Specific Aims are proposed. Aim 1 will determine how NF90 interacts with EZH2 protein to mediate AR gene transcription. Aim 2 will determine how NF90 regulates EZH2 chromatin recruitment and target gene activation using ChIP-seq and RNA-seq assays, characterize downstream genes/pathways of NF90, and examine the expression of NF90 in primary PCa tissues to determine its correlation with EZH2 expression and clinical outcomes. Lastly, Aim 3 will characterize the roles of NF90 in prostate cancer in vitro and in vivo and, most importantly, test the efficacy of a new combinatorial therapeutic approach that simultaneously blocks the dual roles of EZH2 using enzymatic EZH2 inhibitor GSK126 and AR antagonist enzalutamide in PCa patient-derived xenograft (PDX) models.

概括前列腺癌（PCA）是最常见的非皮肤癌，也是第三大领先美国男性癌症死亡的原因。虽然可以有效地处理早期PCA 手术和放射疗法，转移性前列腺癌仍然是一个挑战，雄激素剥夺疗法（ADT）是主要治疗方法。虽然大多数高级PCA 最初对ADT做出良好的反应，他们最终会产生抵抗力并cast割 - 抗性，称为CRPC。 CRPC肿瘤不再需要雄激素才能生长，但通常会保留取决于异常活跃的雄激素受体（AR）。了解机制这种与雄激素无关的AR激活可能会对有效的策略阐明根除CRPC。 EZH2是Polycomb抑制复合物2（PRC2）的酶促亚基催化组蛋白H3赖氨酸27三甲基化以抑制基因表达，这种作用可以通过酶EZH2抑制剂有效地靶向。最近的证据表明EZH2可能在激活基因表达中具有非依赖PRC2的作用。但是，关键差距仍然是对于目标基因是什么，EZH2如何激活它们以及它们如何与 EZH2促进CRPC的表观遗传作用。我们的初步结果表明AR是直接的 EZH2介导的转录激活的靶标。这种激活可能是由EZH2-介导的相互作用的共激活器NF90。我们的初步数据进一步表明，NF90在 CRPC和表现出致癌功能。但是，NF90的角色从未被研究过在PCA中。我们假设NF90与EZH2在AR和AR的转录激活中合作促进CRPC的进展。为了检验这些假设，提出了三个具体目标。目的 1将确定NF90如何与EZH2蛋白相互作用以介导AR基因转录。目标2 将确定NF90如何调节EZH2染色质募集和靶基因激活使用芯片序列和RNA-seq分析，表征了NF90的下游基因/途径，并且检查NF90在原代PCA组织中的表达以确定其与EZH2的相关性表达和临床结果。最后，AIM 3将表征NF90在前列腺中的作用体外和体内癌症，最重要的是，测试新组合的功效使用酶Ezh2同时阻止EZH2的双重作用的治疗方法 PCA患者衍生异种移植物（PDX）中的抑制剂GSK126和AR拮抗剂Enzalutamide 型号。