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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 |
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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. |
doi_str_mv | 10.1002/aac2.12043 |
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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.</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 & 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”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4263-ed5dd71a739da902d37da6a1f6e739c16c9bcfa53fad7ac2fc21bffab7b0f3a13</citedby><cites>FETCH-LOGICAL-c4263-ed5dd71a739da902d37da6a1f6e739c16c9bcfa53fad7ac2fc21bffab7b0f3a13</cites><orcidid>0000-0002-0441-2307</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2615008857/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2615008857?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,11562,25753,27924,27925,37012,37013,44590,46052,46476,74998</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36303712$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Audesse, Amanda J.</creatorcontrib><creatorcontrib>Karashchuk, Galina</creatorcontrib><creatorcontrib>Gardell, Zachary A.</creatorcontrib><creatorcontrib>Lakis, Nelli S.</creatorcontrib><creatorcontrib>Maybury‐Lewis, Sun Y.</creatorcontrib><creatorcontrib>Brown, Abigail K.</creatorcontrib><creatorcontrib>Leeman, Dena S.</creatorcontrib><creatorcontrib>Teo, Yee Voan</creatorcontrib><creatorcontrib>Neretti, Nicola</creatorcontrib><creatorcontrib>Anthony, Douglas C.</creatorcontrib><creatorcontrib>Brodsky, Alexander S.</creatorcontrib><creatorcontrib>Webb, Ashley E.</creatorcontrib><title>FOXO3 regulates a common genomic program in aging and glioblastoma stem cells</title><title>Aging and cancer</title><addtitle>Aging Cancer</addtitle><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.</description><subject>Age</subject><subject>Aging</subject><subject>Brain cancer</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Epigenetics</subject><subject>Genes</subject><subject>Glioma</subject><subject>Kinases</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>Proteins</subject><subject>Stem cells</subject><subject>Transcription factors</subject><subject>transcriptomics</subject><subject>Tumors</subject><issn>2643-8909</issn><issn>2643-8909</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp9kV1rFDEUhoMotqy98QdIwBsRtuZjNtm5EZbFfkBlbxS8CydfY5bMZE1mKv33Zju1tF54lXDy8HDyvgi9peScEsI-ARh2Thlp-At0ykTDl-uWtC-f3E_QWSl7UmFOedPS1-iEC064pOwUfb3Y_dhxnF03RRhdwYBN6vs04M4NqQ8GH3LqMvQ4DBi6MHQYBou7GJKOUMbUAy6j67FxMZY36JWHWNzZw7lA3y--fNteLW92l9fbzc3SNEzwpbMrayUFyVsLLWGWSwsCqBeujgwVptXGw4p7sLL-zxtGtfegpSaeA-ULdD17bYK9OuTQQ75TCYK6H6TcKchjMNEp6zXT0nOqHW9IC1q0RK5p4-Rx7Hl1fZ5dh0n3zho3jBniM-nzlyH8VF26Va0gVNTcF-jDgyCnX5Mro-pDOcYBg0tTUUzWsGvylFT0_T_oPk15qFEpJuiKkPV6JSv1caZMTqVk5x-XoUQdS1fH0tV96RV-93T9R_RvxRWgM_A7RHf3H5XabLZslv4B5qq2mA</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Audesse, Amanda J.</creator><creator>Karashchuk, Galina</creator><creator>Gardell, Zachary A.</creator><creator>Lakis, Nelli S.</creator><creator>Maybury‐Lewis, Sun Y.</creator><creator>Brown, Abigail K.</creator><creator>Leeman, Dena S.</creator><creator>Teo, Yee Voan</creator><creator>Neretti, Nicola</creator><creator>Anthony, Douglas C.</creator><creator>Brodsky, Alexander S.</creator><creator>Webb, Ashley E.</creator><general>John Wiley & Sons, Inc</general><general>Wiley</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>M0R</scope><scope>M0S</scope><scope>NAPCQ</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-0441-2307</orcidid></search><sort><creationdate>202112</creationdate><title>FOXO3 regulates a common genomic program in aging and glioblastoma stem cells</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4263-ed5dd71a739da902d37da6a1f6e739c16c9bcfa53fad7ac2fc21bffab7b0f3a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Age</topic><topic>Aging</topic><topic>Brain cancer</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Epigenetics</topic><topic>Genes</topic><topic>Glioma</topic><topic>Kinases</topic><topic>Metabolism</topic><topic>Mutation</topic><topic>Proteins</topic><topic>Stem cells</topic><topic>Transcription factors</topic><topic>transcriptomics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Audesse, Amanda J.</creatorcontrib><creatorcontrib>Karashchuk, Galina</creatorcontrib><creatorcontrib>Gardell, Zachary A.</creatorcontrib><creatorcontrib>Lakis, Nelli S.</creatorcontrib><creatorcontrib>Maybury‐Lewis, Sun Y.</creatorcontrib><creatorcontrib>Brown, Abigail K.</creatorcontrib><creatorcontrib>Leeman, Dena S.</creatorcontrib><creatorcontrib>Teo, Yee Voan</creatorcontrib><creatorcontrib>Neretti, Nicola</creatorcontrib><creatorcontrib>Anthony, Douglas C.</creatorcontrib><creatorcontrib>Brodsky, Alexander S.</creatorcontrib><creatorcontrib>Webb, Ashley E.</creatorcontrib><collection>Wiley Open Access</collection><collection>Wiley Online Library</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>ProQuest_Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Nursing & Allied Health Premium</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Aging and cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Audesse, Amanda J.</au><au>Karashchuk, Galina</au><au>Gardell, Zachary A.</au><au>Lakis, Nelli S.</au><au>Maybury‐Lewis, Sun Y.</au><au>Brown, Abigail K.</au><au>Leeman, Dena S.</au><au>Teo, Yee Voan</au><au>Neretti, Nicola</au><au>Anthony, Douglas C.</au><au>Brodsky, Alexander S.</au><au>Webb, Ashley E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FOXO3 regulates a common genomic program in aging and glioblastoma stem cells</atitle><jtitle>Aging and cancer</jtitle><addtitle>Aging Cancer</addtitle><date>2021-12</date><risdate>2021</risdate><volume>2</volume><issue>4</issue><spage>137</spage><epage>159</epage><pages>137-159</pages><issn>2643-8909</issn><eissn>2643-8909</eissn><abstract>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.</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>36303712</pmid><doi>10.1002/aac2.12043</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0002-0441-2307</orcidid><oa>free_for_read</oa></addata></record> |
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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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