Role of NF90 in Prostate Cancer

NF90 在前列腺癌中的作用

• 批准号: 10237241
• 负责人: Jindan Yu
• 金额: $ 36.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237241
• 关键词: AR gene; Affinity Chromatography; American; Androgen Receptor; Androgens; Apoptosis; Binding; Biological Assay; Cancer Etiology; 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; Hyperactivity; 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; advanced prostate cancer; androgen deprivation therapy; castration resistant prostate cancer; clinically relevant; combinatorial; efficacy evaluation; efficacy testing; epigenetic silencing; 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; patient derived xenograft model; preclinical study; promoter; prostate cancer cell; prostate carcinogenesis; receptor expression; recruit; targeted treatment; therapeutic target; transcriptome sequencing; tumor; tumor growth

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， 导致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，雄激素 剥夺疗法（ADT）是主要的治疗方法。虽然大多数先进的PCa 最初对ADT反应良好，最终产生耐药性并被阉割- 耐药，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）。了解各种机制， 这种雄激素非依赖性AR激活可能为有效的策略提供重要的启示， 根除CRPC。EZH 2是多梳抑制复合物2（PRC 2）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 被酶促EZH 2抑制剂有效靶向。最近的证据表明，EZH 2可能 在激活基因表达中具有PRC 2-独立的作用。然而，关键的差距仍然存在， 靶基因是什么，EZH 2如何激活它们，以及它们如何与靶基因协同工作。 EZH 2促进CRPC的表观遗传作用。我们的初步结果表明，AR是一种直接的 靶向EZH 2介导的转录激活。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在细胞内表达上调。 CRPC并显示致癌功能。然而，NF 90的作用从未被研究过。 在PCa。我们假设NF 90与EZH 2在AR的转录激活中协同作用， 促进CRPC进展。为了验证这些假设，提出了三个具体目标。目的 1将确定NF 90如何与EZH 2蛋白相互作用以介导AR基因转录。目的2 将决定NF 90如何调节EZH 2染色质募集和靶基因激活 使用ChIP-seq和RNA-seq分析，表征NF 90的下游基因/途径，以及 检测NF 90在原发性PCa组织中的表达，以确定其与EZH 2的相关性 表达和临床结果。最后，目标3将描述NF 90在前列腺中的作用。 癌症在体外和体内，最重要的是，测试一种新的组合的功效， 使用酶促EZH 2同时阻断EZH 2的双重作用的治疗方法 抑制剂GSK 126和AR拮抗剂Enzalutamide在PCa患者来源异种移植物（PDX）中作用 模型