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Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas

Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gl...

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Autores principales: Escoll, Maribel, Lastra, Diego, Pajares, Marta, Robledinos-Antón, Natalia, Rojo, Ana I., Fernández-Ginés, Raquel, Mendiola, Marta, Martínez-Marín, Virginia, Esteban, Isabel, López-Larrubia, Pilar, Gargini, Ricardo, Cuadrado, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016245/
https://www.ncbi.nlm.nih.gov/pubmed/31918259
http://dx.doi.org/10.1016/j.redox.2019.101425
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author Escoll, Maribel
Lastra, Diego
Pajares, Marta
Robledinos-Antón, Natalia
Rojo, Ana I.
Fernández-Ginés, Raquel
Mendiola, Marta
Martínez-Marín, Virginia
Esteban, Isabel
López-Larrubia, Pilar
Gargini, Ricardo
Cuadrado, Antonio
author_facet Escoll, Maribel
Lastra, Diego
Pajares, Marta
Robledinos-Antón, Natalia
Rojo, Ana I.
Fernández-Ginés, Raquel
Mendiola, Marta
Martínez-Marín, Virginia
Esteban, Isabel
López-Larrubia, Pilar
Gargini, Ricardo
Cuadrado, Antonio
author_sort Escoll, Maribel
collection PubMed
description Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program.
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spelling pubmed-70162452020-02-18 Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas Escoll, Maribel Lastra, Diego Pajares, Marta Robledinos-Antón, Natalia Rojo, Ana I. Fernández-Ginés, Raquel Mendiola, Marta Martínez-Marín, Virginia Esteban, Isabel López-Larrubia, Pilar Gargini, Ricardo Cuadrado, Antonio Redox Biol Research Paper Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program. Elsevier 2020-01-02 /pmc/articles/PMC7016245/ /pubmed/31918259 http://dx.doi.org/10.1016/j.redox.2019.101425 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Escoll, Maribel
Lastra, Diego
Pajares, Marta
Robledinos-Antón, Natalia
Rojo, Ana I.
Fernández-Ginés, Raquel
Mendiola, Marta
Martínez-Marín, Virginia
Esteban, Isabel
López-Larrubia, Pilar
Gargini, Ricardo
Cuadrado, Antonio
Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas
title Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas
title_full Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas
title_fullStr Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas
title_full_unstemmed Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas
title_short Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas
title_sort transcription factor nrf2 uses the hippo pathway effector taz to induce tumorigenesis in glioblastomas
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016245/
https://www.ncbi.nlm.nih.gov/pubmed/31918259
http://dx.doi.org/10.1016/j.redox.2019.101425
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