The Role of NOV (CCN3) in Prostate Cancer Progression

NOV (CCN3) 在前列腺癌进展中的作用

• 批准号: 8422066
• 负责人: Jindan Yu
• 金额: $ 32.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422066
• 关键词: Address; Affect; American; Androgen Receptor; Androgens; Binding; Biological Assay; Cancer Etiology; Castration; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Loop; Chromosomes; Data; Development; Diagnosis; Disease; EZH2 gene; Electrophoretic Mobility Shift Assay; Enhancers; Environment; Epigenetic Process; Extracellular Matrix Proteins; Family; Gene Targeting; Genes; Genomics; Growth; Histones; Hormones; Immunoblot Analysis; Immunoblotting; In Vitro; Integrins; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Matrix Metalloproteinases; Measures; Mediating; Meta-Analysis; Metastatic Prostate Cancer; Methylation; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mus; NOV gene; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Organ; PC3 cell line; Pathway interactions; Patients; Play; Polycomb; Prognostic Marker; Property; Prostatic Neoplasms; Proteins; Radiation therapy; Receptor Activation; Receptor Signaling; Recruitment Activity; Regulation; Reporter; Reporting; Repression; Resistance; Role; Sampling; Signal Transduction; Site; Staging; Techniques; Testing; Therapeutic; Tissue Microarray; Tissues; Transcript; Transcription Repressor/Corepressor; Transcriptional Activation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Xenograft procedure; anticancer research; base; cancer diagnosis; cancer initiation; castration resistant prostate cancer; cell motility; chromatin remodeling; deprivation; effective therapy; gene repression; in vivo; innovation; loss of function; men; migration; mouse model; notch protein; novel; novel therapeutics; overexpression; promoter; prostate cancer cell; prostate carcinogenesis; public health relevance; receptor function; response; subcutaneous; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in American men. While organ-confined PCa can be effectively eradicated through surgical and radiation therapies, metastatic disease is essentially incurable. Androgen signaling mediated through the androgen receptor (AR) is one of the most important pathways in PCa initiation and progression. Hormone-deprivation has thus been the standard, first-line treatment for metastatic PCa. Interestingly, in the late-stage castration-resistant PCa (CRPC), AR has become activated, rather than insensitive, in a low androgen environment, thus being responsible for castration resistance. Therefore, understanding and targeting AR pathway remains a central challenge in PCa research. While AR signaling has been studied for decades, it is incompletely understood with past focus largely on genes induced by the AR. Interestingly, recent studies, including ours, have started to show AR also as a globally acting transcriptional repressor. Further, our data suggest that this repression is mediated by the polycomb group protein EZH2 and repressive chromatin remodeling around the target genes. However, a model gene that is representative of this innovative role of AR is needed to further delineate the mechanistic details of AR-mediated repression and, most importantly, to appreciate the functional relevance and therapeutic importance of this repression. Through meta-analysis of androgen-regulated expression microarray data, we nominated NOV (CCN3) as a top candidate. Our preliminary data suggest that NOV is a novel gene of great importance in PCa. It is inhibited by AR and EZH2 and is markedly down-regulated in advanced PCa. Functional analysis suggests that NOV inhibits PCa progression and its loss-of-function drives castration resistance. We thus hypothesize that NOV is directly suppressed by AR through repressive chromatin remodeling and plays essential roles in PCa progression. To address this hypothesis, three specific aims are proposed. In Aim 1, we will determine androgen regulation and NOV expression in prostate cancer, including patient samples. In Aim 2, we will examine how AR inhibits NOV expression in prostate cancer cells. We will determine if AR directly binds to the NOV gene promoter and/or enhancer, map chromatin changes around the gene, and examine whether/how EZH2 is response for these changes and thus gene repression. Aim 3 will investigate the functional role of NOV in regulating PCa proliferation, migration, invasion/metastasis, and castration resistance using cell line models and nude mice.

描述（由申请人提供）：前列腺癌（PCa）是美国男性中最常诊断出的非皮肤癌。虽然局限于器官的前列腺癌可以通过手术和放射治疗有效根除，但转移性疾病基本上是无法治愈的。通过雄激素受体 (AR) 介导的雄激素信号传导是 PCa 起始和进展中最重要的途径之一。因此，激素剥夺已成为转移性前列腺癌的标准一线治疗方法。有趣的是，在晚期去势抵抗性PCa（CRPC）中，AR在低雄激素环境下变得激活，而不是不敏感，从而负责去势抵抗。因此，理解和靶向 AR 通路仍然是 PCa 研究的核心挑战。虽然 AR 信号传导已经研究了几十年，但人们对它的了解并不完全，过去的注意力主要集中在 AR 诱导的基因上。有趣的是，最近的研究，包括我们的研究，已经开始表明 AR 也是一种全球性转录抑制因子。此外，我们的数据表明，这种抑制是由多梳组蛋白 EZH2 和靶基因周围的抑制性染色质重塑介导的。然而，需要一个代表 AR 这种创新作用的模型基因来进一步描述 AR 介导的抑制的机制细节，最重要的是，了解这种抑制的功能相关性和治疗重要性。通过对雄激素调节表达微阵列数据的荟萃分析，我们提名 NOV (CCN3) 作为最佳候选者。我们的初步数据表明 NOV 是 PCa 中非常重要的新基因。它被 AR 和 EZH2 抑制，并且在晚期 PCa 中显着下调。功能分析表明，NOV 抑制 PCa 进展，其功能丧失会导致去势抵抗。因此，我们假设 NOV 通过抑制性染色质重塑被 AR 直接抑制，并在 PCa 进展中发挥重要作用。为了解决这一假设，提出了三个具体目标。在目标 1 中，我们将确定前列腺癌（包括患者样本）中的雄激素调节和 NOV 表达。在目标 2 中，我们将研究 AR 如何抑制前列腺癌细胞中的 NOV 表达。我们将确定 AR 是否直接与 NOV 基因启动子和/或增强子结合，绘制基因周围染色质变化的图谱，并检查 EZH2 是否/如何响应这些变化以及基因抑制。目标 3 将使用细胞系模型和裸鼠研究 NOV 在调节 PCa 增殖、迁移、侵袭/转移和去势抵抗中的功能作用。