AR and RUNX2 target genes in prostate cancer

前列腺癌中的AR和RUNX 2靶点 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。是 这两个过程的联系？前者是由异常雄激素受体（AR）驱动的 信号轴，而后者与成骨细胞特异性转录因子 CaP细胞中的RUNX 2。本项目的目标是识别AR（具体目标#1）和RUNX 2 （具体目标#2）使用新的无偏基因组实验方法在CaP细胞中靶向基因 我们最近开发的方法（称为ChIP Display，CD）。我们预计明年的 鉴定了三组基因，即受AR调节的基因、受RUNX 2调节的基因 以及可能以协同方式由两者调节的那些。后一组基因 可能提供了对骨转移瘤雄激素抵抗机制的深入了解， 在具体目标#4中，我们打算实验性地测试AR/RUNX 2 在靶位点的共占有与基因表达相结合，并从分子上剖析已知的 AR/RUNX 2在结构和功能方面的相互作用。成功完成这些 目的将导致对雄激素的CaP表型的机械理解 独立性和对骨头的偏爱。将检验两个主要假设：（i）雄激素 非依赖性CaP由异常AR或AR/RUNX 2信号通过靶基因驱动， 控制过程，如细胞周期进程，和（ii）前列腺癌的骨偏好 细胞由RUNX 2或RUNX 2/AR靶基因驱动，这些基因控制骨- 特定的拟骨基因，以巩固骨中的细胞生长。

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.