Onco & Cancer Res：袁增强等Hippo信号通路和癌症及细胞衰老研究获进展

Hpo/MST-Yki/YAP通路对于调控细胞生长和器官大小起着非常重要的作用，YAP2（Yes associated protein2）作为该通路的核心蛋白，参与肿瘤的发生发展。中国科学院生物物理研究所袁增强课题组一直关注与研究YAP2的分子调控机制及其在肿瘤发生发展中的功能。其研究成果分别在Oncogene和Cancer Research发表。

2013年4月1日在Oncogene上在线发表的文章报道了YAP2新的分子调控机制在肝癌细胞增殖及耐药性中的作用。YAP2作为原癌蛋白存在多种翻译后修饰（磷酸化和泛素化等），调控其转录活性与功能。研究揭示了YAP2新的翻译后修饰——乙酰化和去乙酰化，鉴定SIRT1作为YAP2的主要去乙酰化酶，增强YAP2与转录因子TEAD4的结合，促进其转录活性，并且在抗肿瘤药物（CDDP）处理下使YAP2入核发挥转录因子的功能，从而增强肝癌细胞的增殖及对抗肿瘤药物的抵抗。与之对应的是，肝癌标本中SIRT1的蛋白水平明显高于正常组织，而且与YAP2的下游靶基因CTGF表达呈明显正相关。这些结果为揭示肝癌的发生发展机制及肝癌的治疗提供了新的依据。

细胞衰老是抑制肿瘤发生的重要机制。袁增强研究组发现YAP2作为原癌蛋白的新功能——抑制衰老。YAP2在复制型衰老的人正常二倍体细胞IMR90中表达下降。YAP2的干扰直接诱导细胞衰老，这一现象是TEAD和Rb/p16/p53通路依赖的。研究发现，CDK6是主要介导YAP2抑制衰老的下游靶基因，被YAP/TEAD转录复合物调控。通过在YAP2干扰的细胞中对CDK6过表达，能够逆转YAP2蛋白下调引起的细胞衰老。除了正常细胞，YAP2蛋白的下调也能明显增强化学药物诱导的肿瘤细胞的衰老，说明YAP2在肿瘤细胞中也具有抗衰老的功能，揭示了YAP2促进肿瘤发生发展的新机制。这一结果于2013年4月在线发表在Cancer Research上。

上述研究得到科技部及国家自然科学基金委的资助。

与细胞衰老相关的拓展阅读：

• Nat Rev Immunol：CD4辅助1细胞可诱导肿瘤细胞衰老
• Science：美发现极端长寿蛋白 为细胞衰老提供新视角
• 细胞衰老不能阻止肿瘤的生长
更多信息请点击：有关细胞衰老更多资讯

doi:10.1038/onc.2013.88
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SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma

B Mao, F Hu, J Cheng, P Wang, M Xu, F Yuan, S Meng, Y Wang, Z Yuan and W Bi

The MST/YAP (mammalian Ste20-like kinase/Yes-associated protein 2) pathway plays an important role in hepatocellular carcinoma (HCC). Although post-translational modification—especially MST/Lats (large tumor suppressor)-mediated phosphorylation and PP1 (protein phosphatase-1)-mediated dephosphorylation—has been found to regulate the activity of YAP2, very little is known about its acetylation. In our experiments, we observed that the expression of SIRT1 is significantly upregulated in the tumor samples of the hepatocarcinoma patients, and SIRT1 mRNA level positively correlates with connective tissue growth factor (CTGF) mRNA level. We then found that SIRT1 deacetylates YAP2 protein in HCC cells and SIRT1-mediated deacetylation increases the YAP2/TEAD4 association, leading to YAP2/TEAD4 transcriptional activation and upregulated cell growth in HCC cells. Moreover, knockdown of SIRT1 blocks the cisplatin (CDDP)-induced nuclear translocation of YAP2 and enhances the chemosensitivity of HCC cells to CDDP treatment. Together, our findings reveal a new regulatory mechanism of YAP2 by the SIRT1-mediated deacetylation that may be involved in HCC tumorigenesis and drug resistance.

doi:10.1158/0008-5472.CAN-12-3793
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YAP/TEAD-mediated transcription controls cellular senescence

Qi Xie1, Jing Chen2, Han Feng3, Shengyi Peng4, Ursula Adams5, Yujie Bai1, Li Huang1, Ji Li6, Junjian Huang7, Zengqiang Yuan8,*, and Songshu Meng9

Transcription co-activator YAP plays an important role in the regulation of cell proliferation and apoptosis. Here, we identify a new role of YAP in the regulation of cellular senescence. We find that the expression levels of YAP proteins decrease following the replication-induced cellular senescence in IMR90 cells. Silencing of YAP inhibits cell proliferation and induces premature senescence. In additional experiments, we observe that cellular senescence induced by YAP deficiency is TEAD- and Rb/p16/p53- dependent. Furthermore, we show that Cdk6 is a direct downstream target gene of YAP in the regulation of cellular senescence, and the expression of Cdk6 is through the YAP-TEAD complex. Ectopic expression of Cdk6 rescued YAP knockdown-induced senescence. Finally, we find that down-regulation of YAP in tumor cells increases senescence in response to chemotherapeutic agents and YAP or Cdk6 expression rescues cellular senescence. Taken together, our findings define the critical role of YAP in the regulation of cellular senescence and provide a novel insight into a potential chemotherapeutic avenue for tumor suppression.