VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex
VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex
复制标题
VGLL4 通过负向调节 YAP-TEAD 转录复合物作为肺癌中的新肿瘤抑制因子
DOI：
10.1038/cr.2014.10
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发表时间：
2014-03-01
期刊：
影响因子：
44.1
通讯作者：
Ji, Hongbin
中科院分区：
文献类型：
--
作者：
Zhang, Wenjing;Gao, Yijun;Ji, Hongbin
肺癌是世界范围内最具破坏性的疾病之一，具有高发病率和高死亡率。Hippo（Hpo）途径是果蝇和哺乳动物器官大小的保守调节因子。新出现的证据表明Hpo通路在癌症发展中的重要性。在这项研究中，我们确定VGLL 4作为一种新的肿瘤抑制剂在肺癌的发生，通过负调控YAP-TEAD复合物的形成，Hpo途径的核心组成部分。我们的数据显示，VGLL 4在小鼠和人肺癌标本中经常观察到低表达。VGLL 4的异位表达在体外显著抑制肺癌细胞的生长。更重要的是，VGLL 4在从头小鼠模型中显著抑制肺癌进展。我们进一步发现VGLL 4抑制YAP-TEAD转录复合物的活性。我们的数据表明，VGLL 4直接与雅普竞争结合TEAD，并通过两个TDU结构域执行其生长抑制功能。总的来说，我们的研究表明，VGLL 4是一种新的肺癌肿瘤抑制因子，通过负调节YAP-TEAD复合物的形成，从而Hpo途径。
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.