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

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
Entity
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)
Publisher
Elsevier B.V.
Date
2020-01-02
Citation
10.1016/j.redox.2019.101425
Redox Biology 30 (2020): 101425
 
 
 
ISSN
2213-2317/
DOI
10.1016/j.redox.2019.101425
Funded by
This study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) under the grant SAF2016-76520-R. ME is recipient of a postdoctoral contract Juan de la Cierva; DL and NRA of a FPU contract of MINECO; MP and RFG of a FPI contracts of Autonomous University of Madrid. RG has been funded by the AECC Scientific Foundation.
Project
Gobierno de España. SAF2016-76520-R
Editor's Version
https://doi.org/10.1016/j.redox.2019.101425
Subjects
Oxidative stress; Cancer stem cells; Chemotherapy; Glioblastoma; Medicina
URI
http://hdl.handle.net/10486/692727
Rights
© 2020 The Authors

Licencia de Creative Commons
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional.

Abstract

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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Google™ Scholar: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

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  • Producción científica en acceso abierto de la UAM [14677]

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