El Yousfi, YounesMora-Molina, RocíoLópez-Rivas, AbelardoYerbes, Rosario2025-02-252025-02-252023-09-27El Yousfi, Y., Mora-Molina, R., López-Rivas, A. y Yerbes, R. (2023). Role of the yap/taz-tead transcriptional complex in the metabolic control of trail sensitivity by the mevalonate pathway in cancer cells. Cells, 12 (19), 2370. https://doi.org/10.3390/cells12192370.2073-4409https://hdl.handle.net/11441/169363Different studies have reported that inhibiting the mevalonate pathway with statins may increase the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although the signaling mechanism leading to this sensitization remains largely unknown. Weinvestigated the role of the YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex in the metabolic control of TRAIL sensitivity by the mevalonate pathway. We show that depleting nuclear YAP/TAZ in tumor cells, either via treatment with statins or by silencing YAP/TAZ expression with siRNAs, facilitates the activation of apoptosis by TRAIL. Furthermore, the blockage of TEAD transcriptional activity either pharmacologically or through the ectopic expression of a disruptor of the YAP/TAZ interaction with TEADtranscription factors, overcomes the resistance of tumor cells to the induction of apoptosis by TRAIL. Our results show that the mevalonate pathway controls cellular the FLICE-inhibitory protein (cFLIP) expression in tumor cells. Importantly, inhibiting the YAP/TAZ-TEAD signaling pathwayinducescFLIPdown-regulation, leading to a marked sensitization of tumor cells to apoptosis induction by TRAIL. Our data suggest that a combined strategy of targeting TEAD activity and selectively activating apoptosis signaling by agonists of apoptotic TRAIL receptors could be explored as a potential therapeutic approach in cancer treatment.application/pdf19 p.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/StatinsMevalonate pathwayTNF-related apoptosis-inducing ligandYAP/TAZ-TEADCellular FLICE-like inhibitory proteininfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.3390/cells12192370