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. RNA-seq data of 293AD cells expressing vector control or FLAG-YAP 5SA, subjected to (or not) overnight (14 h) serum deprivation