AR and RUNX2 target genes in prostate cancer

前列腺癌中的 AR 和 RUNX2 靶基因

• 批准号: 7048041
• 负责人: Gerhard A Coetzee
• 金额: $ 31.71万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048041
• 关键词: androgen receptor; androgens; bioinformatics; biological signal transduction; bone neoplasms; cell line; chromatin immunoprecipitation; gene expression; hormone related neoplasm /cancer; metastasis; neoplasm /cancer genetics; osteoblasts; prostate neoplasms; protein protein interaction; protein structure function; transcription factor

DESCRIPTION (provided by applicant): AR and RUNX2 targets in prostate cancer. Fatal prostate cancer (CaP) is typified by androgen independence and metastasis to bone. Are the two processes linked? The former is driven by an aberrant androgen receptor (AR) signaling axis, while the latter is associated with the osteoblast-specific transcription factor RUNX2 in CaP cells. The goal of this project is to identify AR (specific aim #1) and RUNX2 (specific aim #2) target genes in CaP cells using a novel, unbiased genomic experimental approach, which we have recently developed (called ChIP Display, CD). We predict the identification of three groups of genes, those regulated by AR, those regulated by RUNX2 and those regulated by both, possibly in a synergistic manner. The latter group of genes might provide insight into mechanisms that govern androgen resistance of bone metastatic deposits (specific aim #3). In specific aim #4 we intend to experimentally test AR/RUNX2 co-occupancy at target sites coupled with gene expression and molecularly dissect the known AR/RUNX2 interactions in structural and functional terms. Successful completion of these aims will lead to a mechanistic understanding of the CaP phenotypes of androgen independence and predilection to bone. Two main hypotheses will be tested: (i) Androgen independent CaP is driven by aberrant AR or AR/RUNX2 signaling through target genes that control processes such as cell cycle progression, and (ii) bone predilection of prostate cancer cells is driven by RUNX2 or RUNX2/AR target genes that control the expression of bone- specific, osteomimetic genes to consolidate cell growth in bone.

描述（由申请人提供）：前列腺癌中的 AR 和 RUNX2 靶标。 致命性前列腺癌（CaP）的特点是雄激素依赖性和骨转移。这两个过程有联系吗？前者由异常雄激素受体 (AR) 信号轴驱动，而后者与 CaP 细胞中成骨细胞特异性转录因子 RUNX2 相关。该项目的目标是使用我们最近开发的一种新颖、无偏见的基因组实验方法（称为 ChIP Display，CD）来识别 CaP 细胞中的 AR（特定目标 #1）和 RUNX2（特定目标 #2）靶基因。我们预测鉴定出三组基因，即受 AR 调节的基因、受 RUNX2 调节的基因以及受两者调节的基因，可能以协同方式进行。后一组基因可能有助于深入了解控制骨转移沉积物雄激素抵抗的机制（具体目标#3）。在具体目标#4中，我们打算通过实验测试AR/RUNX2在靶位点的共占用以及基因表达，并从结构和功能方面对已知的AR/RUNX2相互作用进行分子剖析。成功完成这些目标将导致对雄激素独立性和对骨骼的偏好的 Cap 表型的机械理解。将测试两个主要假设：(i) 雄激素非依赖性 CaP 是由异常 AR 或 AR/RUNX2 信号传导通过控制细胞周期进展等过程的靶基因驱动的，以及 (ii) 前列腺癌细胞的骨偏好是由 RUNX2 或 AR/RUNX2 驱动的RUNX2/AR 靶基因控制骨特异性、拟骨基因的表达，以巩固骨中的细胞生长。