AR and RUNX2 target genes in prostate cancer

描述（由申请人提供）：AR和RUNX2在前列腺癌中的靶点。致死性前列腺癌（CaP）的典型特征是雄激素不依赖性和骨转移。这两个过程有联系吗？前者由异常雄激素受体（AR）信号轴驱动，而后者与CaP细胞中成骨特异性转录因子RUNX2相关。该项目的目标是使用我们最近开发的一种新颖的、无偏倚的基因组实验方法（称为ChIP Display， CD）来鉴定CaP细胞中的AR（特定目标#1）和RUNX2（特定目标#2）靶基因。我们预测鉴定出三组基因，即由AR调控的基因，由RUNX2调控的基因和由两者调控的基因，可能以协同方式进行。后一组基因可能提供对控制骨转移沉积物雄激素抗性机制的见解（特定目的#3）。在具体目标#4中，我们打算通过实验测试AR/RUNX2在靶位点与基因表达的共占用，并从结构和功能方面对已知的AR/RUNX2相互作用进行分子解剖。这些目标的成功完成将导致对雄激素依赖性和骨偏好的CaP表型的机制理解。本文将测试两个主要假设：(i)雄激素非依赖性CaP是由异常AR或AR/RUNX2信号通过靶基因控制细胞周期进程驱动的；（ii）前列腺癌细胞的骨偏好是由RUNX2或RUNX2/AR靶基因驱动的，这些基因控制骨特异性、拟骨基因的表达，以巩固骨中的细胞生长。

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.