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HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model

Sex differences are evident in the incidence, therapeutic response and survival of patients with various cancers including the most common, aggressive and incurable GBM. We generated a murine GBM model of male and female astrocytes with dual loss of NF1 and P53 that yielded a sex-biased transformati...

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Autores principales: Abou-Antoun, Tamara, Kfoury, Najla, Yang, Lihua, Warrington, Nicole, Chen, Xuhua, Reiss, India, Wilkinson, Michael, Mitra, Robi, Rubin, Josh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164955/
http://dx.doi.org/10.1093/neuonc/noac079.240
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author Abou-Antoun, Tamara
Kfoury, Najla
Yang, Lihua
Warrington, Nicole
Chen, Xuhua
Reiss, India
Wilkinson, Michael
Mitra, Robi
Rubin, Josh
author_facet Abou-Antoun, Tamara
Kfoury, Najla
Yang, Lihua
Warrington, Nicole
Chen, Xuhua
Reiss, India
Wilkinson, Michael
Mitra, Robi
Rubin, Josh
author_sort Abou-Antoun, Tamara
collection PubMed
description Sex differences are evident in the incidence, therapeutic response and survival of patients with various cancers including the most common, aggressive and incurable GBM. We generated a murine GBM model of male and female astrocytes with dual loss of NF1 and P53 that yielded a sex-biased transformation of the astrocytes with male cells being significantly more tumorigenic and therapeutically resistant compared to female cells. In our current work, we aimed to delineate the molecular mechanisms driving this sex-biased tumorigenic phenotype in order to deliver therapies that are more effective to patients with GBM. We examined the inhibition of KLF5 on tumorigenic phenotypes using cellular bio-functional assays. We used barcoded transposon calling cards to determine the genomic localization of KLF5 and the differentially induced gene expression in male versus female GBM cells. Chemical inhibition or shRNA knock-down of KLF5 significantly reduced proliferation, migration, clonogenic stem-cell frequency and survival, but increase apoptosis in male and female GBM cells. Interestingly, male, but not female, GBM cells exhibited an increased migratory phenotype after radiation that inhibition of KLF5 significantly reduced. Moreover, KLF5 inhibition significantly reduced the protein expression of tumorigenic PDGFRB, AKT, ERK and the stem marker Sox-2. Transposon calling cards mapped unique KLF5 genomic localization in male versus female GBM cells with significantly differential gene expression profiles between the two. The top genes induced by KLF5 in male cells were primarily affiliated with poorer prognosis and reduced survival, whereas in female cells they were affiliated with better prognosis and improved survival in patients with cancer. Our findings provide a promising exploratory avenue for KLF5 as a therapeutic target in GBM and warrants further investigation in order to delineate the precise molecular mechanisms driving this antitumor response so that targeted therapy would be more effective taking into consideration the sex-differences in patients with GBM.
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spelling pubmed-91649552022-06-05 HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model Abou-Antoun, Tamara Kfoury, Najla Yang, Lihua Warrington, Nicole Chen, Xuhua Reiss, India Wilkinson, Michael Mitra, Robi Rubin, Josh Neuro Oncol High Grade Glioma Sex differences are evident in the incidence, therapeutic response and survival of patients with various cancers including the most common, aggressive and incurable GBM. We generated a murine GBM model of male and female astrocytes with dual loss of NF1 and P53 that yielded a sex-biased transformation of the astrocytes with male cells being significantly more tumorigenic and therapeutically resistant compared to female cells. In our current work, we aimed to delineate the molecular mechanisms driving this sex-biased tumorigenic phenotype in order to deliver therapies that are more effective to patients with GBM. We examined the inhibition of KLF5 on tumorigenic phenotypes using cellular bio-functional assays. We used barcoded transposon calling cards to determine the genomic localization of KLF5 and the differentially induced gene expression in male versus female GBM cells. Chemical inhibition or shRNA knock-down of KLF5 significantly reduced proliferation, migration, clonogenic stem-cell frequency and survival, but increase apoptosis in male and female GBM cells. Interestingly, male, but not female, GBM cells exhibited an increased migratory phenotype after radiation that inhibition of KLF5 significantly reduced. Moreover, KLF5 inhibition significantly reduced the protein expression of tumorigenic PDGFRB, AKT, ERK and the stem marker Sox-2. Transposon calling cards mapped unique KLF5 genomic localization in male versus female GBM cells with significantly differential gene expression profiles between the two. The top genes induced by KLF5 in male cells were primarily affiliated with poorer prognosis and reduced survival, whereas in female cells they were affiliated with better prognosis and improved survival in patients with cancer. Our findings provide a promising exploratory avenue for KLF5 as a therapeutic target in GBM and warrants further investigation in order to delineate the precise molecular mechanisms driving this antitumor response so that targeted therapy would be more effective taking into consideration the sex-differences in patients with GBM. Oxford University Press 2022-06-03 /pmc/articles/PMC9164955/ http://dx.doi.org/10.1093/neuonc/noac079.240 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle High Grade Glioma
Abou-Antoun, Tamara
Kfoury, Najla
Yang, Lihua
Warrington, Nicole
Chen, Xuhua
Reiss, India
Wilkinson, Michael
Mitra, Robi
Rubin, Josh
HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
title HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
title_full HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
title_fullStr HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
title_full_unstemmed HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
title_short HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
title_sort hgg-25. targeting klf5 reduces tumorigenic phenotype in a murine glioblastoma (gbm) model
topic High Grade Glioma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164955/
http://dx.doi.org/10.1093/neuonc/noac079.240
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