AR and RUNX2 target genes in prostate cancer

前列腺癌中的 AR 和 RUNX2 靶基因

• 批准号: 7541446
• 负责人: Gerhard A Coetzee
• 金额: $ 25.28万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541446
• 关键词: Androgen Receptor; Androgens; Biochemical; Bioinformatics; Cell Cycle Progression; Cell Proliferation; Cells; Coupled; Deposition; Disease; Gene Expression; Gene Targeting; Genes; Genomics; Goals; Growth; Homing; Human; LAPC4; LNCaP; Laboratories; Lead; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Neoplasm Metastasis; Osteoblasts; Osteocalcin; PC3 cell line; Phenotype; Process; Proteins; Receptor Signaling; Reporting; Research Personnel; Resistance; Role; Signal Transduction; Site; Skeleton; Surface; Techniques; Testing; Tissues; bone; cancer cell; cell growth; chromatin immunoprecipitation; insight; novel; osteopontin; programs; promoter; tool; transcription factor; tumor progression

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 identity 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.

前列腺癌中的 AR 和 RUNX2 靶点 致命性前列腺癌（CaP）的特点是雄激素依赖性和骨转移。是 两个进程有联系吗？前者由异常雄激素受体 (AR) 驱动 信号轴，而后者与成骨细胞特异性转录因子相关 CaP 细胞中的 RUNX2。该项目的目标是识别 AR（具体目标#1）和 RUNX2 （具体目标#2）使用新颖的、公正的基因组实验来确定 CaP 细胞中的靶基因 我们最近开发了一种方法（称为 ChIP Display，CD）。我们预测 鉴定三组基因，受 AR 调节的基因，受 RUNX2 调节的基因 以及受两者监管的，可能以协同的方式。后一组基因 可能有助于深入了解控制骨转移雄激素抵抗的机制 存款（具体目标 #3）。在具体目标 #4 中，我们打算通过实验测试 AR/RUNX2 目标位点的共占据与基因表达相结合并从分子角度剖析已知的 AR/RUNX2 在结构和功能方面的相互作用。顺利完成这些 目标将导致对雄激素的 Cap 表型的机械理解 独立性和对骨骼的偏爱。将测试两个主要假设：(i) 雄激素 独立的 CaP 由异常 AR 或 AR/RUNX2 信号通过靶基因驱动， 控制过程，例如细胞周期进展和 (ii) 前列腺癌的骨倾向 细胞由控制骨表达的 RUNX2 或 RUNX2/AR 靶基因驱动 特定的拟骨基因可巩固骨骼中的细胞生长。