雄激素阻断是目前治疗晚期前列腺癌的主要手段，去势治疗出现抵抗后是导致患者死亡的根源。因此，寻找其他途径抑制前列腺癌细胞的生长及转化将成为治疗前列腺癌的突破方向。在前期多组学研究基础上，筛选验证了PAK2蛋白在去势抵抗性前列腺癌（CRPC）组织中被激活。提出科学假说：去势治疗后，雄激素受体（AR）结合DNA甲基化酶形成复合体对PAK2基因表达抑制作用降低，而PAK2结合β-catenin调节前列腺上皮干/祖细胞生长，导致CRPC的形成。本项目拟采用前列腺上皮特异性PAK2基因敲除的前列腺癌小鼠模型和人前列腺癌组织前列腺原位种植小鼠模型为研究对象。运用实验动物学和表观遗传学的研究手段，明确AR复合体引起PAK2启动子区的甲基化而抑制PAK2表达的机制；PAK2结合β-catenin调节Wnt信号系统进而调节前列腺上皮干/祖细胞的生长。证实PAK2作为CRPC药物治疗靶向分子的应用价值。

Androgen deprivation therapy(ADT) is the main treatment of advanced prostate cancer, but the castration resistant progression of later stage prostate cancer is responsible for patient’s death. Therefore, to find other ways to inhibit prostate cancer cell growth and transformation will be breakthrough in the treatment of prostate cancer. Based on the previous screening studies of proteomics and Genomics, we proved that the PAK2 protein, plays a pivotal role in the formation of castration resistant prostate cancer (CRPC).We hypothesized that PAK2 gene expression is under the negative regulation of androgen receptor (AR)complex with DNMT, and is increased following the ADT; PAK2 activation is a crucial step for the prostate epithelial cell cancer stem/progenitor cells growth, which are previously reported as the potential cause for CRPC. In this proposal, we are going to adopt the prostate epithelial-specific PAK2 knockout tumor mice and human prostate cancer specimen xenograft mice, using the laboratory methods and tools in experimental zoology, epigenetics and bioinformatics, to demonstrate that (a) AR complex methylate the promoter of PAK2 gene and suppress PAK2 expression; (b) PAK2 regulates Wnt activity by binding β-catenin, which results in directing the prostate epithelial cell cancer stem/progenitor cells proliferation. Above all, we are going to testify that PAK2 is valuable to be treated as a target for CRPC management.