前列腺癌中转录共激活子TAZ的基因转录调控机制及其功能研究

We found that TAZ, the downstream transcriptional co-activator regulated by Hippo pathway, is prostate basal cell maker. Compared to the androgen dependent luminal type prostate cancer cells LNCaP and 22Rv1, TAZ is highly expressed in the androgen independent basal type prostate cancer cells DU145 and PC3, which could be due to the high mRNA level of TAZ. However, the transcriptional mechanism of TAZ and the biological function of TAZ in the prostate cancer are still obscure. In this study, we will explore the transcriptional regulation mechanism of TAZ in the prostate cancer cells and study the biological effects of TAZ overexpression in prostate cancer. RNA-seq combined with ChIP-seq will be performed to screen the direct targets of TAZ in the prostate cancer cells and further studies will determine the biological function of TAZ mediated by these direct target genes. Last, the correlation between clinicopathological characteristics and TAZ upstream transcription factors, TAZ, TAZ downstream target will be explored, including the prognostic value of these factors. Our study will reveal the transcriptional regulation mechanism of TAZ and illustrate transcriptional dysregulation mechanism of TAZ to promote tumorigenesis and progression in prostate cancer, providing the potential biomarkers and drug targets for the diagnosis and treatment of prostate cancer.

前期研究发现，Hippo信号通路下游转录共激活子TAZ是正常前列腺基底细胞的分子标记物，与雄性激素依赖的管腔型前列腺癌细胞LNCaP和22Rv1相比，TAZ在雄性激素非依赖的基底型细胞DU145和PC3中高表达，TAZ高表达与基因转录相关，然而TAZ的基因转录调控机制及其在前列腺癌中高表达的生物学意义都不明确。本课题拟研究前列腺癌细胞中TAZ的基因转录调控机制，研究TAZ高表达对前列腺癌细胞生物学功能的影响，通过RNA-seq和ChIP-seq筛选前列腺癌细胞中TAZ下游直接靶基因，明确哪些靶基因介导TAZ的生物学功能，并在临床样本中研究TAZ上游转录因子、TAZ、TAZ下游靶基因与临床病理资料和预后的相关性。通过本研究，揭示TAZ的基因转录调控机制，阐明TAZ的基因转录失调导致TAZ高表达进而促进前列腺癌发生、发展的分子机制，为前列腺癌的临床诊断与治疗提供潜在的分子标记物和药物靶点。

Hippo信号通路失活导致下游转录共激活子YAP/TAZ活性增强，与肿瘤的发生、发展有着密切联系。既往Hippo信号通路的研究主要集中在Hippo信号通路相关的翻译后修饰调控上，而对Hippo信号通路成员的转录调控机制研究较少。同时，既往研究主要聚焦转录共激活子YAP与前列腺癌发生、发展的关系，而TAZ在前列腺癌中的作用还未有深入研究。通过本项目的研究，我们发现Hippo信号通路下游转录共激活子TAZ是正常前列腺上皮基底细胞的分子标记物，在雄性激素非依赖型的前列腺癌细胞中，TAZ的转录水平显著升高，而前列腺癌相关转录因子ETV1/4/5调控TAZ的基因转录。在前列腺癌细胞中，TAZ与肿瘤细胞迁移、肿瘤转移密切相关，过表达TAZ促进前列腺正常上皮细胞的上皮细胞向间充质细胞的转化以及细胞迁移，在前列腺癌细胞中敲减TAZ则抑制了癌细胞的细胞迁移和肿瘤转移；细胞迁移相关基因SH3BP1是前列腺癌中介导TAZ促细胞迁移的下游关键直接靶基因。本研究揭示了前列腺癌细胞中转录共激活子TAZ的mRNA转录调控机制，明确了前列腺癌细胞中调控TAZ基因转录的转录因子，阐明TAZ在前列腺癌中的转录激活机制,在转录水平阐明了Hippo信号通路的新调控机制。同时还阐明了TAZ与前列腺癌发生、发展以及雄性激素非依赖的关系，明确TAZ对下游关键靶基因SH3BP1的调控，为前列腺癌的临床诊断、预后判断提供新的分子标记物和潜在的药物作用靶点。