精氨酸甲基转移酶PRMT4通过催化TEAD甲基化调控Hippo-YAP信号通路的分子机制及其在神经胶质母细胞瘤中的作用

The Hippo pathway regulates organ size ,stem cell homeostasis and tumorigenesis via balancing cell proliferation, apoptosis and differentiation. TEAD-YAP complex controls most of transcriptional output of Hippo pathway. As aberrant TEADs-YAP activity has been proved to be closely related to Glioblastoma tumorigenesis and progression, exploring mechanisms of TEAD-YAP activity regulation is of great significance in improving targeted therapy. We found that PRMT4 regulats TEAD arginine methylation and affects TEAD-YAP activity. Therefore, we will try to reveal its function in glioma progression and its molecular mechanism. We will use Glioblastoma cell lines and mouse Glioblastoma model to study the function of TEAD related PRMTs in proliferation, apoptosis ,cancer stem cell renewal and tumorigenic ability. Our study will hopefully provide important therapeutic strategies against Glioblastoma.

Hippo信号通路协同调控细胞增殖、凋亡及分化，在器官大小发育、干细胞稳态维持和肿瘤发生发展过程中至关重要。TEAD-YAP复合体活性决定Hippo信号通路大部分转录输出。研究表明TEAD-YAP复合体活性异常升高与神经胶质母细胞瘤发生发展密切相关，因此探索TEAD-YAP复合体活性调控机制中对推进胶质瘤靶向治疗具有积极意义。前期研究发现精氨酸甲基转移酶PRMT4可以催化TEAD精氨酸甲基化并且影响TEAD-YAP复合体活性，因此推测PRMT4介导的精氨酸甲基化修通过调控TEAD-YAP复合体活性影响胶质瘤发生发展。我们将利用胶质瘤细胞系、裸鼠胶质瘤模型及胶质瘤病理芯片分别在细胞水平、动物水平和病理水平阐明PRMT4介导的TEAD甲基化对胶质瘤增殖、凋亡、肿瘤干细胞自我更新及成瘤能力的影响并明确分子机制。此项研究将为建立新的胶质瘤靶向治疗策略及药物研发提供指导。

Hippo信号通路协同调控细胞增殖及凋亡以维持细胞稳态，在器官大小发育和肿瘤发生发展过程中至关重要。TEAD-YAP复合体活性决定Hippo信号通路大部分转录输出。研究表明TEAD-YAP复合体活性异常升高与神经胶质瘤发生发展密切相关，因此探索TEAD-YAP复合体活性调控机制中对推进胶质瘤靶向治疗具有积极意义。我们研究发现TEAD1-4在体内和体外均能发生精氨酸甲基化；通过质谱发现TEAD3的第55位精氨酸能发生单甲基化修饰；通过Co-IP和体外甲基化实验证明PRMT4和PRMT6是直接甲基化TEAD的精氨酸甲基化酶；通过transwell实验证明TEAD精氨酸甲基化位点突变影响胶质瘤细胞的转移能力；RNA-seq发现TEAD3 R55K影响转移相关基因的表达。综上，本研究揭示了TEAD甲基化对胶质瘤细胞转移能力的影响并明确分子机制。此项研究将为建立新的胶质瘤靶向治疗策略及药物研发提供指导。