Zhang Wenjing, Gao Yijun, Li Peixue, Shi Zhubing, Guo Tong, Li Fei, Han Xiangkun, Feng Yan, Zheng Chao, Wang Zuoyun, Li Fuming, Chen Haiquan, Zhou Zhaocai, Zhang Lei, Ji Hongbin
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Yueyang Road, Shanghai 200031, China.
1] Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China [2] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Cell Res. 2014 Mar;24(3):331-43. doi: 10.1038/cr.2014.10. Epub 2014 Jan 24.
Lung cancer is one of the most devastating diseases worldwide with high incidence and mortality. Hippo (Hpo) pathway is a conserved regulator of organ size in both Drosophila and mammals. Emerging evidence has suggested the significance of Hpo pathway in cancer development. In this study, we identify VGLL4 as a novel tumor suppressor in lung carcinogenesis through negatively regulating the formation of YAP-TEAD complex, the core component of Hpo pathway. Our data show that VGLL4 is frequently observed to be lowly expressed in both mouse and human lung cancer specimens. Ectopic expression of VGLL4 significantly suppresses the growth of lung cancer cells in vitro. More importantly, VGLL4 significantly inhibits lung cancer progression in de novo mouse model. We further find that VGLL4 inhibits the activity of the YAP-TEAD transcriptional complex. Our data show that VGLL4 directly competes with YAP in binding to TEADs and executes its growth-inhibitory function through two TDU domains. Collectively, our study demonstrates that VGLL4 is a novel tumor suppressor for lung cancer through negatively regulating the YAP-TEAD complex formation and thus the Hpo pathway.
肺癌是全球最具毁灭性的疾病之一，发病率和死亡率都很高。Hippo（Hpo）信号通路是果蝇和哺乳动物中保守的器官大小调节因子。新出现的证据表明Hpo信号通路在癌症发展中具有重要意义。在本研究中，我们通过负向调节Hpo信号通路的核心成分YAP-TEAD复合物的形成，确定VGLL4是肺癌发生过程中的一种新型肿瘤抑制因子。我们的数据表明，在小鼠和人类肺癌标本中，经常观察到VGLL4低表达。异位表达VGLL4可显著抑制体外肺癌细胞的生长。更重要的是，VGLL4在小鼠肺癌原发模型中显著抑制肺癌进展。我们进一步发现VGLL4抑制YAP-TEAD转录复合物的活性。我们的数据表明，VGLL4在与TEADs结合时直接与YAP竞争，并通过两个TDU结构域发挥其生长抑制功能。总之，我们的研究表明，VGLL4是一种新型的肺癌肿瘤抑制因子，它通过负向调节YAP-TEAD复合物的形成从而调节Hpo信号通路。
