AR and RUNX2 target genes in prostate cancer

描述(申请人提供)：前列腺癌的AR和RUNX2靶点。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。这两个过程有关联吗？前者由一个异常的雄激素受体(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。这个项目的目标是使用我们最近开发的一种新的、无偏见的基因组实验方法(称为芯片显示，CD)来识别CAP细胞中的AR(特异性目的#1)和RUNX2(特异性目的#2)靶基因。我们预测了三组基因的识别，那些由AR调控的基因，那些由RUNX2调控的基因，以及那些由两者共同调控的基因，可能是以协同的方式。后一组基因可能为控制骨转移沉积雄激素抵抗的机制提供洞察力(具体目标#3)。在特定的目标#4中，我们打算在实验上测试AR/RUNX2在靶点的共占性与基因表达的耦合，并从分子上剖析已知的AR/RUNX2在结构和功能方面的相互作用。这些目标的成功完成将导致对雄激素独立性和对骨的偏好的帽子表型的机械性理解。将检验两个主要假说：(I)雄激素非依赖性CAP由异常的AR或AR/RUNX2信号通过控制细胞周期进程等过程的靶基因驱动，以及(Ii)前列腺癌细胞的骨偏好由RUNX2或RUNX2/AR靶基因驱动，RUNX2或RUNX2/AR靶基因控制骨特异的拟骨基因的表达，以巩固细胞在骨中的生长。

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.