原癌蛋白YAP2的分子调控在肿瘤发生发展中的作用和机制研究

Hippo/MST-Yorkie/YAP signaling pathway plays an important role in the regulation of the cell growth and organ size control. As the core effector, YAP2(Yes associated protein2) is critical for tumorigenesis.Previous reports indicate that the post-translational modifications of YAP2 including phosphorylation, sumoylation, ubiqutination, regulate the transcriptional activity and proto-oncogenic function of YAP2, indicating the post-translational modification plays an important role in the YAP2-mediated tumorigenesis. Our preliminary date indicated that YAP2 could be acetylated and deacetylated by SIRT1 both in vitro and in vivo. We also observed that YAP2 regulated glucose consumption and lactate production in hepatocarcinoma cells, suggesting that YAP2 may participate in glucose metabolism in tumor cells. Based on these observations, we aim to further identify the acetylaton of YAP2 both in cell lines and clinical specimens of hepatocarcinoma, and to elucidate the role and molecular mechanism of YAP2's acetylation/deacetylation in regulating glucose metabolism and tumorigenesis, with the implication of a novel therapeutic avenue for the treatment of liver cancer.

Hpo/MST-Yki/YAP通路对于调控细胞生长和器官大小有重要作用，YAP2（Yes associated protein2）作为该通路的核心蛋白参与肿瘤的发生发展。以往的研究表明YAP2的翻译后修饰（磷酸化和泛素化等）调控其转录活性与功能，提示YAP2蛋白的翻译后修饰在YAP2介导的肿瘤发生中有重要作用。我们前期工作发现，YAP2存在乙酰化修饰，去乙酰化酶SIRT1能对YAP2去乙酰化加强YAP2的转录活性，并观察到YAP2能调节肝癌细胞的葡萄糖消耗和乳酸代谢，提示YAP2可能在肿瘤糖代谢中具有重要作用。在此基础上，本项目将进一步鉴定YAP2的乙酰化修饰，研究乙酰化和去乙酰化修饰对YAP2的功能调控，并在肝癌临床标本中加以验证；同时检测YAP2及其乙酰化修饰在肿瘤糖代谢中的作用，阐明YAP2的分子调控引起肿瘤细胞代谢异常的分子机制，为靶向于能量代谢的肿瘤治疗提高理论依据。

Hpo/MST-Yki/YAP通路对于调控细胞生长和器官大小有重要作用，YAP 作为该通路的核心蛋白参与肿瘤的发生发展。以往的研究表明YAP的翻译后修饰（磷酸化和泛素化等）调控其转录活性与功能，提示YAP蛋白的翻译后修饰在YAP介导的肿瘤发生中有重要作用。我们工作发现，YAP存在乙酰化修饰，去乙酰化酶SIRT1能对YAP去乙酰化加强YAP的转录活性，促进YAP和TEAD的相互作用及下游基因的表达，从而参与肝癌细胞的增殖及耐药性。. 另外，我们发现缺氧时，YAP的上游调控蛋白LATS1/2被降解，YAP的磷酸化水平降低，从而被诱导入核。入核后的YAP结合到HK2的启动子上，促进HK2的表达，引起肿瘤细胞的无氧糖酵解及无氧条件下的细胞增殖。在人的乳腺癌标本中，我们检测到YAP与HK2的表达呈明显正相关，进一步验证了YAP和HK2在调控肿瘤发生发展中的相关性。我们的结果揭示了原癌蛋白YAP的新的调控方式及调控肿瘤发生发展的新机制，为靶向于能量代谢的肿瘤治疗提高理论依据。