YAP promotes global mRNA translation to fuel oncogenic growth despite starvation

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies. This research investigates how cells manage their size and proliferation by coordinating two signaling pathways, Hippo and mTOR. As these pathways are fundamental for normal development, their dysregulation results in numerous diseases, including many cancers. In particular, the study aims to understand how YAP and TAZ—effectors of the Hippo pathway—influence mTOR-mediated protein synthesis in cells, a previously unclear process. Surprisingly, our findings show that YAP and TAZ can maintain active protein synthesis even when cells are deprived of nutrients in both cultured cells and mice. Since self-sufficiency in growth signals is a key hallmark of cancer, targeting this axis could serve as a novel and effective therapeutic strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.