Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells

Different 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. We investigated...

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Detalles Bibliográficos
Autores: El Yousfi, Younes, Mora-Molina, Rocío, López-Rivas, Abelardo, Yerbes, Rosario
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/347039
Acceso en línea:http://hdl.handle.net/10261/347039
https://api.elsevier.com/content/abstract/scopus_id/85173897794
Access Level:acceso abierto
Palabra clave:TNF-related apoptosis-inducing ligand
YAP/TAZ-TEAD
Cellular FLICE-like inhibitory protein
Mevalonate pathway
Statins
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spelling Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer CellsEl Yousfi, YounesMora-Molina, RocíoLópez-Rivas, AbelardoYerbes, RosarioTNF-related apoptosis-inducing ligandYAP/TAZ-TEADCellular FLICE-like inhibitory proteinMevalonate pathwayStatinsDifferent 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. We investigated 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 TEAD transcription 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 pathway induces cFLIP down-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.This work was supported by grants from Ministerio de Ciencia e Innovación (PGC2018-093960-B-I00 and PID2021-122226NB-I00), Junta de Andalucía (PY20-00754) and the European Community through the regional development funding program (FEDER) to ALR.Peer reviewedMolecular Diversity Preservation InternationalMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Junta de AndalucíaEuropean CommissionMora-Molina, Rocío [0000-0001-7256-732X]López-Rivas, Abelardo [0000-0002-9351-9690]Yerbes, Rosario [0000-0002-4372-7619]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/347039https://api.elsevier.com/content/abstract/scopus_id/85173897794reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-093960-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122226NB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at https://doi.org/10.3390/cells12192370https://doi.org/10.3390/cells12192370Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3470392026-05-22T06:33:51Z
dc.title.none.fl_str_mv Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
title Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
spellingShingle Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
El Yousfi, Younes
TNF-related apoptosis-inducing ligand
YAP/TAZ-TEAD
Cellular FLICE-like inhibitory protein
Mevalonate pathway
Statins
title_short Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
title_full Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
title_fullStr Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
title_full_unstemmed Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
title_sort Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells
dc.creator.none.fl_str_mv El Yousfi, Younes
Mora-Molina, Rocío
López-Rivas, Abelardo
Yerbes, Rosario
author El Yousfi, Younes
author_facet El Yousfi, Younes
Mora-Molina, Rocío
López-Rivas, Abelardo
Yerbes, Rosario
author_role author
author2 Mora-Molina, Rocío
López-Rivas, Abelardo
Yerbes, Rosario
author2_role author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Junta de Andalucía
European Commission
Mora-Molina, Rocío [0000-0001-7256-732X]
López-Rivas, Abelardo [0000-0002-9351-9690]
Yerbes, Rosario [0000-0002-4372-7619]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv TNF-related apoptosis-inducing ligand
YAP/TAZ-TEAD
Cellular FLICE-like inhibitory protein
Mevalonate pathway
Statins
topic TNF-related apoptosis-inducing ligand
YAP/TAZ-TEAD
Cellular FLICE-like inhibitory protein
Mevalonate pathway
Statins
description Different 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. We investigated 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 TEAD transcription 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 pathway induces cFLIP down-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.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/347039
https://api.elsevier.com/content/abstract/scopus_id/85173897794
url http://hdl.handle.net/10261/347039
https://api.elsevier.com/content/abstract/scopus_id/85173897794
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-093960-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122226NB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at https://doi.org/10.3390/cells12192370
https://doi.org/10.3390/cells12192370
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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