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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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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. |
format | Online Article Text |
id | pubmed-7016245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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