受雄激素信号调节的YAP1蛋白在去势抵抗性前列腺癌增殖中的作用

The castration resistant progression of later stage prostate cancer is responsible for patient's death. Based on the previous screening studies of phosphor-proteomics genechips and siRNA-chips, we proved that the YAP1 protein, a key factor in Hippo pathway, plays a pivotal role in the formation of castration resistant prostate cancer (CRPC).We hypothesized that YAP1 gene expression is under the negative regulation of androgen receptor (AR), and is increased following the androgen deprivation therapy (ADT); YAP1 activation is a crucial step for the prostate epithelial cell dedifferentiation from luminal-like cancer cells to cancer stem/progenitor cells, which are previously reported as the potential cause for CRPC. In this proposal, we are going to adopt the prostate epithelial-specific YAP1 knockout tumor mice and human prostate cancer specimen xenograft mice, using the laboratory methods and tools in experimental zoology, epigenetics, molecular biology and bioinformatics, to demonstrate that (a) AR binds EZH2 to recruit DNMT3A to methylate the promoter of YAP1 gene and suppresses YAP1 expression; (b) YAP1 regulates AKT activity by phosphorylation, which results in mTOR and p70S6K expression; (c)YAP1 directs the prostate epithelial cell dedifferentiation via OCT4 and SOX2 gene regulations. Above all, we are going to testify that YAP1 is valuable to be treated as a target for CRPC management.

晚期前列腺癌对去势治疗出现抵抗后,疾病进展是导致患者死亡的根源。在前期多组学研究的基础上，筛选并初步验证了Hippo信号通路的关键开关蛋白YAP1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，雄激素受体对YAP1基因表达的抑制作用降低，而YAP1调节了前列腺上皮细胞向干/祖细胞的逆分化是CRPC形成的关键。本项目拟采用前列腺上皮特异性YAP1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、表观遗传学和分子生物学的研究手段，明确雄激素受体通过结合EZH2而召集DNMT3A，引起YAP1启动子区的甲基化而抑制YAP1的表达； YAP1通过调节AKT磷酸化进而调节mTOR及P70S6K的表达；并且YAP1调节干细胞基因OCT4，SOX2的表达而调节了前列腺上皮细胞的逆分化。证实YAP1作为CRPC药物治疗靶向分子的应用价值。

晚期前列腺癌对去势治疗出现抵抗后,疾病进展是导致患者死亡的根源。在前期多组学研究的基础上，筛选并初步验证了Hippo信号通路的关键开关蛋白YAP1在去势抵抗性前列腺癌（CRPC）组织中被激活,作为靶点蛋白能够有效治疗肿瘤。结果发表在oncogene、oncotarget杂志上。在此基础上，提出一新的治疗方案：在前列腺癌病人去势治疗的基础上联合YAP1的抑制剂veteprofin克服肿瘤干祖细胞生长，达到有效治疗前列腺癌的目的。初步体外实验证实：雄激素受体通过结合EZH2而召集DNMT3A，引起YAP1启动子区的甲基化而抑制YAP1的表达，去势治疗后，雄激素受体对YAP1基因表达的抑制作用降低，而YAP1调节了前列腺上皮细胞向干/祖细胞的逆分化是CRPC形成的关键。进而我们利用前列腺上皮basel细胞敲除YAP1鼠，证实前列腺上皮敲除YAP1后抑制前列腺癌干祖细胞的生长进而抑制了前列腺癌CRPC的进展。本项目是对以往治疗方案的优化与创新，更接近临床，将为前列腺癌治疗开辟一种新方法。