YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [293AD]

The Hippo pathway downstream effectors YAP and TAZ display oncogenic potential via their transcriptional co-activator function, mediated primarily by binding to TEAD transcription factors. Many studies have focused on identifying YAP/TAZ-TEAD target genes, but their role in the regulation of protein synthesis has remained largely unexplored. Here we show that YAP activation is sufficient to overcome the global translation restriction of 5?TOP-containing mRNAs, which is induced by serum deprivation and dependent on the inactivation of mTORC1. We found that YAP/TAZ repressed the expression of DDIT4, a negative regulator of mTORC1 whose expression is otherwise upregulated by serum deprivation. Forced expression of DDIT4 was sufficient to suppress translation and transformative potential of serum-unresponsive uveal melanoma cells, which harbor G protein mutations. Our findings highlight crosstalk between Hippo-YAP/TAZ and mTORC1 pathways in the regulation of translation and offer a new perspective towards understanding YAP/TAZ-driven malignancies. Overall design: RNA-seq data of 293AD cells expressing vector control or FLAG-YAP 5SA, subjected to (or not) overnight (14 h) serum deprivation

Hippo信号通路（Hippo pathway）的下游效应因子YAP与TAZ主要通过结合TEAD转录因子（TEAD transcription factors）发挥转录共激活功能，进而展现致癌潜能。既往大量研究聚焦于YAP/TAZ-TEAD复合物的靶基因鉴定，但二者在蛋白质合成调控中的作用仍未得到充分阐释。本研究证实，YAP激活足以克服由血清剥夺诱导、且依赖mTORC1（雷帕霉素复合物1）失活的含5'末端寡聚嘧啶（5'TOP）mRNA的全局翻译抑制。我们发现，YAP/TAZ可抑制DNA损伤诱导转录因子4（DDIT4）的表达——DDIT4是mTORC1的负调控因子，其表达通常会在血清剥夺条件下被上调。强制表达DDIT4足以抑制携带G蛋白突变的血清无响应性葡萄膜黑色素瘤细胞的翻译能力与致瘤转化潜能。本研究揭示了Hippo-YAP/TAZ与mTORC1通路在翻译调控中的交叉调控关系，为理解YAP/TAZ驱动的恶性肿瘤提供了全新视角。
整体实验设计：本研究的RNA测序（RNA-seq）数据取自转染空载对照或FLAG标签融合YAP 5SA突变体的293AD细胞，分别经（或不经）14小时过夜血清剥夺处理。