转录因子BTF3促进去势抵抗性前列腺癌恶性生长的分子机制研究

去势抵抗性前列腺癌（CRPC）缺乏有效治疗方案且致死率高，探寻影响CRPC发生发展的关键异变基因对分子靶向治疗意义重大。申请人前期发现，敲低转录因子BTF3可有效抑制CRPC细胞PC-3增殖、迁移及侵袭能力并促进凋亡。进一步研究发现，下调BTF3导致G2／M期阻滞、DNA断裂及其损伤应激蛋白ATM表达减少；前列腺癌数据库中BTF3与雌激素受体ERα表达显著正相关，敲低BTF3增加PC-3细胞对ERα抑制剂他莫昔芬的敏感性，而对ERα阴性DU145细胞并无影响。由此推测，BTF3可能通过调控DNA损伤修复或ERα信号通路促进CRPC细胞恶性生长。基于此，本项目拟通过ChIP-Seq结合RNA-Seq，深入发掘PC-3细胞中BTF3转录调控的关键靶基因及信号通路，并结合CRPC组织芯片和小鼠移植瘤模型，阐明并验证转录因子BTF3促进CRPC恶性生长的分子机制，为临床靶向治疗CRPC提供新思路。

Castration resistant prostate cancer (CRPC) is lack of effective treatment and is associated with high mortality, thus exploring the impact of driver alterations that contribute to the progression of CRPC is of great significance in developing molecular targeted therapy. Our preliminary results revealed that knockdown of transcription factor BTF3 effectively resulted in attenuated proliferation, migration and invasion potential as well as enhanced apoptosis of CRPC PC-3 cells. Our further studies showed that down-regulation of BTF3 resulted in G2 / M arrest , DNA damage and downregulated the expression of DNA damage sensor ATM. In addition, our analysis of the prostate cancer database revealed a positive correlation between the expression of BTF3 and estrogen receptor alpha (ERα). Furthermore, knockdown of BTF3 sensitized PC-3 cells, but not ERα negative DU145 cells, to ERαinhibitor Tamoxifen. Built upon these findings, we hypothesized that BTF3 may promote the malignant growth of CRPC cells through regulating DNA damage repair or ERα signaling pathway. To test this hypothesis, we proposed to use ChIP-Seq in combined with RNA-Seq analyses to identify potential transcriptional target genes of BTF3 and their associated signaling pathway in PC-3 cells, Meanwhile we will employ tissue array newly made with clinical samples and xenograft mouse models of CRPC samples to validate the underlying molecular mechanism of how transcription factor BTF3 promotes the malignant growth of CRPC. This project will provide novel insights to the design of molecular targeted therapy in the treatment of CRPC.