Role of NF90 in Prostate Cancer

NF90 在前列腺癌中的作用

• 批准号: 10862368
• 负责人: Jindan Yu
• 金额: $ 28.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10862368
• 关键词: Role; NF90; Prostate; Cancer

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，也是第三大癌症原因 美国男性的死亡人数。虽然早期 PCa 可以通过手术和放射治疗有效治疗， 转移性前列腺癌仍然是一个挑战，雄激素剥夺疗法（ADT）是主流 治疗。尽管大多数晚期 PCa 最初对 ADT 反应良好，但他们最终会发展为 抵抗并产生去势抵抗，称为 CRPC。 CRPC肿瘤不再需要雄激素来生长，但 通常仍然依赖于异常活跃的雄激素受体（AR）。了解机制 这种不依赖雄激素的 AR 激活可能为根除 CRPC 的有效策略提供重要启示。 EZH2 是多梳抑制复合物 2 (PRC2) 的酶亚基，可催化组蛋白 H3 赖氨酸 27 三甲基化抑制基因表达，EZH2 酶可以有效靶向这一作用 抑制剂。最近的证据表明 EZH2 在激活基因方面可能具有不依赖 PRC2 的作用 表达。然而，关于靶基因是什么、EZH2 如何激活它们以及如何激活它们，仍然存在关键差距。 它们与 EZH2 的表观遗传作用协同作用，促进 CRPC。我们的初步结果表明 AR 是 EZH2 介导的转录激活的直接靶标。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 和 CRPC 中表达上调 表现出致癌功能。然而，NF90 在 PCa 中的作用从未被研究过。我们假设 NF90 与 EZH2 合作参与 AR 的转录激活并促进 CRPC 进展。测试 根据这些假设，提出了三个具体目标。目标 1 将确定 NF90 如何与 EZH2 相互作用 介导 AR 基因转录的蛋白质。目标 2 将确定 NF90 如何调节 EZH2 染色质 使用 ChIP-seq 和 RNA-seq 检测进行招募和靶基因激活，表征下游 NF90 的基因/通路，并检查原发性 PCa 组织中 NF90 的表达以确定其 与 EZH2 表达和临床结果的相关性。最后，《目标 3》将描述 NF90 在 前列腺癌的体外和体内研究，最重要的是测试新组合疗法的功效 使用 EZH2 酶抑制剂 GSK126 和 AR 同时阻断 EZH2 双重作用的方法 PCa 患者来源的异种移植 (PDX) 模型中的拮抗剂恩杂鲁胺。