AR and RUNX2 target genes in prostate cancer

前列腺癌中的 AR 和 RUNX2 靶基因

• 批准号: 7172585
• 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/7172585
• 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 neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Neoplasm Metastasis; Numbers; Osteoblasts; Osteocalcin; PC3 cell line; Phenotype; Process; Proteins; Rate; Receptor Signaling; Reporting; Research Personnel; Resistance; Role; Signal Transduction; Site; Skeleton; Surface; Techniques; Testing; Tissues; bone; bone sialoprotein; cancer cell; cell growth; chromatin immunoprecipitation; insight; novel; osteopontin; programs; promoter; tool; transcription factor; tumor progression

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RUNX 2靶标。 致死性前列腺癌（CaP）的典型特征是雄激素非依赖性和骨转移。这两个过程是否有联系？前者由异常雄激素受体（AR）信号轴驱动，而后者与CaP细胞中的成骨细胞特异性转录因子RUNX 2相关。该项目的目标是使用我们最近开发的一种新的无偏基因组实验方法（称为ChIP Display，CD）鉴定CaP细胞中的AR（特异性目标#1）和RUNX 2（特异性目标#2）靶基因。我们预测识别三组基因，AR调节的基因，RUNX 2调节的基因和两者调节的基因，可能以协同的方式。后一组基因可能提供对骨转移性沉积物的雄激素抵抗机制的了解（具体目标#3）。在具体目标#4中，我们打算通过实验检测AR/RUNX 2在靶位点的共占据与基因表达，并从结构和功能方面对已知的AR/RUNX 2相互作用进行分子剖析。这些目标的成功完成将导致对雄激素非依赖性和骨偏好的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由异常AR或AR/RUNX 2信号传导通过控制过程（例如细胞周期进展）的靶基因驱动，和（ii）前列腺癌细胞的骨偏好由RUNX 2或RUNX 2/AR靶基因驱动，所述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。