A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation.
A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation.
复制标题
TEAD4 的剪接异构体减弱 Hippo-YAP 信号传导以抑制肿瘤增殖
DOI：
10.1038/ncomms11840
复制
发表时间：
2016-06-13
影响因子：
16.6
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Qi Y;Yu J;Han W;Fan X;Qian H;Wei H;Tsai YH;Zhao J;Zhang W;Liu Q;Meng S;Wang Y;Wang Z
异常剪接经常在癌症中发现，但这种改变的生物学后果大多是不确定的。在这里，我们报告说，Hippo-YAP信号，一个关键的途径，调节细胞增殖和器官大小，是在剪接开关的控制下。我们表明，TEAD 4，介导海马雅普信号的转录因子，经历由肿瘤抑制因子RBM 4促进的选择性剪接，产生截短的同种型，TEAD 4-S，其缺乏N-末端DNA结合结构域，但保持雅普相互作用结构域。TEAD 4-S位于细胞核和细胞质中，作为雅普活性的显性负性同种型。因此，TEAD 4-S在癌细胞中减少，其再表达抑制癌细胞增殖和迁移，抑制异种移植小鼠模型中的肿瘤生长。此外，TEAD 4-S在人类癌症中降低，TEAD 4-S水平升高的患者生存率提高。总之，这些数据揭示了一个剪接开关，用于微调Hippo-YAP通路。 发现Hippo/雅普信号通路在多种癌症中失调。在这里，作者揭示了雅普调节的另一种机制，该机制通过TEAD 4的交替剪接同种型发生，TEAD 4作为YAP-TEAD信号传导的显性负调节剂。
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo–YAP signalling, a key pathway that regulates cell proliferation and organ size, is under control of a splicing switch. We show that TEAD4, the transcription factor that mediates Hippo–YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo–YAP pathway. The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.