BRD9在去势抵抗性前列腺癌发生发展中的作用和机制研究

本课题组前期报道了PADI2介导的瓜氨酸化可促进前列腺癌(PCa)转变为去势抵抗性前列腺癌(CRPC)，最近发现BRD9是PADI2的潜在作用底物，但在PCa病变中的作用和机制未知。BRD9通过识别和结合乙酰化组蛋白或非组蛋白从而调控DNA的转录和修复等过程，初步数据显示：BRD9在CRPC组织、长期雄激素剥夺条件下的PCa细胞及其诱导成的肿瘤干细胞中表达水平均显著升高；BRD9可加快PCa细胞增殖、激活雄激素受体(AR)信号通路并促进干细胞形成(涉及AR非依赖)，推测BRD9可通过调控AR依赖和非依赖途径促进CRPC发生发展。本课题拟明确BRD9在CRPC进展中的表达特征及功能；阐明BRD9对AR信号通路和PCa干细胞的调控效应；鉴定BRD9上下游调控分子并证明其与PADI2的关系，构建围绕BRD9和PADI2的“个性化”调控网络；评价检测BRD9表达的临床诊断价值及其抑制剂的干预效果。

Our group has previously reported that PADI2-mediated citrullination could promote castration-resistant prostate cancer (CRPC) progression and, most recently, we identified BRD9 as its potential enzymatic substrate. However, little is known about the role of BRD9 in CRPC. BRD9 harbors a single bromodomain (BD), an epigenetic reader domain that recognizes acetylated lysines on histones and non-histone proteins, and is implicated in DNA replication and transcription and so on. Our preliminary data showed that the expression levels of BRD9 increased significantly in both CRPC tissues and PCa cells when placed under long-term androgen-deprivation condition. Besides, BRD9 expression was also up-regulated in the induced PCa stem cells. Furthermore, BRD9 promoted the proliferation of PCa cells and was implicated in the regulation of AR activity and stem cell induction. These data suggest that BRD9 may promote CRPC progression through androgen receptor (AR) dependent as well as AR independent ways (induction/maintenance of tumor stem cell). This project aims to characterize the expression and biological phenotype of BRD9 in CRPC progression; determine the effects of BRD9 on AR signaling pathway and PCa stem cells, identify the potential regulatory factors up- and downstream of BRD9; analyze the inter relation as well as its underlying mechanisms between BRD9 and PADI2, establish the transcription program and individualized regulation network involving BRD9 and PADI2; evaluate the diagnostic value of BRD9 in clinical biopsy samples and explore the possibility using BRD9 inhibitor as a novel therapeutic approach to treat CRPC.