AR and RUNX2 target genes in prostate cancer

前列腺癌中AR和RUNX2靶点的研究 致命性前列腺癌(CAP)的典型特征是雄激素非依赖性和骨转移。是 这两个过程有联系吗？前者是由异常的雄激素受体(AR)驱动的 信号轴，而后者与成骨细胞特异性转录因子相关 在CAP单元中运行2。本项目的目标是识别AR(特定目标#1)和RUNX2 (特定目标2)使用一种新的、无偏见的基因组实验在CAP细胞中靶向基因 方法，这是我们最近开发的(称为芯片显示，CD)。我们预测 AR调控、RUNX2调控的三组基因的鉴定 以及由两者监管的那些，可能是以协同的方式。后一组基因 可能有助于了解骨转移瘤雄激素抵抗的机制 存款(特定目标#3)。在特定目标#4中，我们打算通过实验测试AR/RUNX2 靶点共占与基因表达和分子解剖已知基因 AR/RUNX2在结构和功能方面的相互作用。成功完成这些任务 AIMS将导致对雄激素帽表型的机械性理解 独立性和嗜好于骨头。将检验两个主要假说：(I)雄激素 独立的CAP是由通过靶基因的AR或AR/RUNX2异常信号驱动的 控制过程，如细胞周期进展，和(Ii)前列腺癌的骨倾向 细胞是由RUNX2或RUNX2/AR靶基因驱动的，这些基因控制着骨- 特定的仿骨基因，以巩固骨骼中的细胞生长。

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.