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FOXO3 regulates a common genomic program in aging and glioblastoma stem cells

Background Glioblastoma (GBM) is an aggressive, age‐associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well know...

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Published in:Aging and cancer 2021-12, Vol.2 (4), p.137-159
Main Authors: Audesse, Amanda J., Karashchuk, Galina, Gardell, Zachary A., Lakis, Nelli S., Maybury‐Lewis, Sun Y., Brown, Abigail K., Leeman, Dena S., Teo, Yee Voan, Neretti, Nicola, Anthony, Douglas C., Brodsky, Alexander S., Webb, Ashley E.
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container_title Aging and cancer
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creator Audesse, Amanda J.
Karashchuk, Galina
Gardell, Zachary A.
Lakis, Nelli S.
Maybury‐Lewis, Sun Y.
Brown, Abigail K.
Leeman, Dena S.
Teo, Yee Voan
Neretti, Nicola
Anthony, Douglas C.
Brodsky, Alexander S.
Webb, Ashley E.
description Background Glioblastoma (GBM) is an aggressive, age‐associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Aims Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. Methods and results We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM‐derived GSCs. Using RNA‐seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3‐regulated pathways are associated with altered mitochondrial functions in both aging and GBM. Conclusions This work identifies a FOXO‐associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.
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These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Aims Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. Methods and results We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM‐derived GSCs. Using RNA‐seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3‐regulated pathways are associated with altered mitochondrial functions in both aging and GBM. Conclusions This work identifies a FOXO‐associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.</description><identifier>ISSN: 2643-8909</identifier><identifier>EISSN: 2643-8909</identifier><identifier>DOI: 10.1002/aac2.12043</identifier><identifier>PMID: 36303712</identifier><language>eng</language><publisher>United States: John Wiley &amp; Sons, Inc</publisher><subject>Age ; Aging ; Brain cancer ; Cancer ; Cell cycle ; Epigenetics ; Genes ; Glioma ; Kinases ; Metabolism ; Mutation ; Proteins ; Stem cells ; Transcription factors ; transcriptomics ; Tumors</subject><ispartof>Aging and cancer, 2021-12, Vol.2 (4), p.137-159</ispartof><rights>2021 The Authors. published by Wiley Periodicals, Inc.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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subjects Age
Aging
Brain cancer
Cancer
Cell cycle
Epigenetics
Genes
Glioma
Kinases
Metabolism
Mutation
Proteins
Stem cells
Transcription factors
transcriptomics
Tumors
title FOXO3 regulates a common genomic program in aging and glioblastoma stem cells
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