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HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells

Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxi...

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Autores principales: Carcelén, María, Velásquez, Carlos, Vidal, Veronica, Gutierrez, Olga, Fernandez-Luna, Jose L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775595/
https://www.ncbi.nlm.nih.gov/pubmed/35054927
http://dx.doi.org/10.3390/ijms23020741
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author Carcelén, María
Velásquez, Carlos
Vidal, Veronica
Gutierrez, Olga
Fernandez-Luna, Jose L.
author_facet Carcelén, María
Velásquez, Carlos
Vidal, Veronica
Gutierrez, Olga
Fernandez-Luna, Jose L.
author_sort Carcelén, María
collection PubMed
description Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. Herein, we have further studied the transcriptional regulation of ODZ1 in GBM stem cells (GSCs) under hypoxic conditions and analyzed whether HIF2α has any role in this regulation. Methods: We performed the experiments in three primary GSC cell lines established from tumor specimens. GSCs were cultured under hypoxia, treated with HIF regulators (DMOG, chetomin), or transfected with specific siRNAs, and the expression levels of ODZ1 and HIF2α were analyzed. In addition, the response of the ODZ1 promoter cloned into a luciferase reporter plasmid to the activation of HIF was also studied. Results: The upregulation of both mRNA and protein levels of HIF2α under hypoxia conditions correlated with the expression of ODZ1 mRNA. Moreover, the knockdown of HIF2α by siRNAs downregulated the expression of ODZ1. We found, in the ODZ1 promoter, a HIF consensus binding site (GCGTG) 1358 bp from the transcription start site (TSS) and a HIF-like site (CCGTG) 826 bp from the TSS. Luciferase assays revealed that the stabilization of HIF by DMOG resulted in the increased activity of the ODZ1 promoter. Conclusions: Our data indicate that the HIF2α-mediated upregulation of ODZ1 helps strengthen the transcriptional control of this migration factor under hypoxia in glioblastoma stem cells. The discovery of this novel transcriptional pathway identifies new targets to develop strategies that may avoid GBM tumor invasion and recurrence.
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spelling pubmed-87755952022-01-21 HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells Carcelén, María Velásquez, Carlos Vidal, Veronica Gutierrez, Olga Fernandez-Luna, Jose L. Int J Mol Sci Article Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. Herein, we have further studied the transcriptional regulation of ODZ1 in GBM stem cells (GSCs) under hypoxic conditions and analyzed whether HIF2α has any role in this regulation. Methods: We performed the experiments in three primary GSC cell lines established from tumor specimens. GSCs were cultured under hypoxia, treated with HIF regulators (DMOG, chetomin), or transfected with specific siRNAs, and the expression levels of ODZ1 and HIF2α were analyzed. In addition, the response of the ODZ1 promoter cloned into a luciferase reporter plasmid to the activation of HIF was also studied. Results: The upregulation of both mRNA and protein levels of HIF2α under hypoxia conditions correlated with the expression of ODZ1 mRNA. Moreover, the knockdown of HIF2α by siRNAs downregulated the expression of ODZ1. We found, in the ODZ1 promoter, a HIF consensus binding site (GCGTG) 1358 bp from the transcription start site (TSS) and a HIF-like site (CCGTG) 826 bp from the TSS. Luciferase assays revealed that the stabilization of HIF by DMOG resulted in the increased activity of the ODZ1 promoter. Conclusions: Our data indicate that the HIF2α-mediated upregulation of ODZ1 helps strengthen the transcriptional control of this migration factor under hypoxia in glioblastoma stem cells. The discovery of this novel transcriptional pathway identifies new targets to develop strategies that may avoid GBM tumor invasion and recurrence. MDPI 2022-01-11 /pmc/articles/PMC8775595/ /pubmed/35054927 http://dx.doi.org/10.3390/ijms23020741 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Carcelén, María
Velásquez, Carlos
Vidal, Veronica
Gutierrez, Olga
Fernandez-Luna, Jose L.
HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
title HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
title_full HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
title_fullStr HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
title_full_unstemmed HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
title_short HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells
title_sort hif2α upregulates the migration factor odz1 under hypoxia in glioblastoma stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775595/
https://www.ncbi.nlm.nih.gov/pubmed/35054927
http://dx.doi.org/10.3390/ijms23020741
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