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.

总结 前列腺癌（PCa）是最常见的非皮肤癌，也是第三大癌症病因 美国男性的死亡虽然早期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，雄激素剥夺治疗（ADT）是主要的治疗方法。 治疗虽然大多数晚期PCa最初对ADT反应良好，但最终发展为 并成为去势抵抗，称为CRPC。CRPC肿瘤不再需要雄激素来生长， 通常依赖于异常活跃的雄激素受体（AR）。了解各种机制， 这种雄激素非依赖性AR激活可能为根除CRPC的有效策略提供重要的线索。 EZH 2是多梳抑制复合物2（PRC 2）的酶亚基，其催化组蛋白H3赖氨酸 27三甲基化抑制基因表达，酶促EZH 2可以有效靶向的作用 抑制剂的最近的证据表明，EZH 2可能具有PRC 2独立的作用，在激活基因 表情然而，关于靶基因是什么，EZH 2如何激活它们，以及如何激活它们， 它们与EZH 2的表观遗传作用协同作用以促进CRPC。我们的初步结果显示， AR是EZH 2介导的转录激活的直接靶标。这种激活可能是由EZH 2介导的。 相互作用的共激活因子NF 90。我们的初步数据进一步表明，NF 90在CRPC中上调， 具有致癌功能。然而，NF 90在PCa中的作用从未被研究过。我们假设 NF 90与EZH 2在AR的转录激活中协同作用并促进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NF 90如何与EZH 2相互作用 蛋白介导AR基因转录。目的2将确定NF 90如何调节EZH 2染色质 使用ChIP-seq和RNA-seq测定的募集和靶基因活化，表征下游 NF 90的基因/途径，并检查NF 90在原发性PCa组织中的表达，以确定其 EZH 2表达与临床结局的相关性。最后，目标3将描述NF 90在以下方面的作用： 前列腺癌在体外和体内，最重要的是，测试一种新的组合治疗的功效， 使用酶促EZH 2抑制剂GSK 126和AR同时阻断EZH 2的双重作用的方法 在PCa患者来源的异种移植物（PDX）模型中的拮抗剂Enzalutamide。