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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) 是最常诊断的非皮肤癌，也是第三大癌症美国男性癌症死亡的原因。虽然早期 PCa 可以有效治疗手术和放射治疗、转移性前列腺癌仍然是一个挑战，而雄激素剥夺疗法（ADT）是主要治疗方法。尽管大多数晚期 PCa 最初对 ADT 反应良好，但最终产生耐药性并被阉割—— 耐药性，称为CRPC。 CRPC 肿瘤不再需要雄激素来生长，但通常仍然存在依赖于异常活跃的雄激素受体（AR）。了解机制这种不依赖于雄激素的 AR 激活可能为有效策略提供重要启示根除CRPC。 EZH2 是 Polycomb 抑制复合物 2 (PRC2) 的酶亚基催化组蛋白 H3 赖氨酸 27 三甲基化以抑制基因表达，这一作用可以被酶 EZH2 抑制剂有效靶向。最近的证据表明 EZH2 可能在激活基因表达方面具有不依赖 PRC2 的作用。然而，关键差距仍然存在目标基因是什么、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 是一种直接 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剂 NF90。我们的初步数据进一步表明 NF90 在 CRPC 并表现出致癌功能。然而，NF90 的作用从未被研究过在前列腺癌中。我们假设 NF90 与 EZH2 合作参与 AR 的转录激活和促进 CRPC 进展。为了检验这些假设，提出了三个具体目标。目的图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 染色质招募和靶基因激活使用 ChIP-seq 和 RNA-seq 测定，表征 NF90 的下游基因/通路，以及检查原发性 PCa 组织中 NF90 的表达以确定其与 EZH2 的相关性表达和临床结果。最后，目标 3 将描述 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 同时阻断 EZH2 双重作用的治疗方法 PCa 患者来源的异种移植物 (PDX) 中的抑制剂 GSK126 和 AR 拮抗剂恩杂鲁胺模型。