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HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma
Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxi...
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Published in: | Cell death discovery 2024-07, Vol.10 (1), p.338-12, Article 338 |
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creator | Contenti, J. Guo, Y. Larcher, M. Mirabal-Ortega, L. Rouleau, M. Irondelle, M. Tiroille, V. Mazzu, A. Duranton-Tanneur, V. Pedeutour, F. Ben-Sahra, I. Lago, C. Leva, G. Tiberi, L. Robert, G. Pouponnot, C. Bost, F. Mazure, N. M. |
description | Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2’s transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity. |
doi_str_mv | 10.1038/s41420-024-02100-5 |
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M.</creator><creatorcontrib>Contenti, J. ; Guo, Y. ; Larcher, M. ; Mirabal-Ortega, L. ; Rouleau, M. ; Irondelle, M. ; Tiroille, V. ; Mazzu, A. ; Duranton-Tanneur, V. ; Pedeutour, F. ; Ben-Sahra, I. ; Lago, C. ; Leva, G. ; Tiberi, L. ; Robert, G. ; Pouponnot, C. ; Bost, F. ; Mazure, N. M.</creatorcontrib><description>Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2’s transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.</description><identifier>ISSN: 2058-7716</identifier><identifier>EISSN: 2058-7716</identifier><identifier>DOI: 10.1038/s41420-024-02100-5</identifier><identifier>PMID: 39048564</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154/53/2423 ; 631/443/319/320 ; 631/67/1857 ; 631/67/2332 ; 631/80/82/23 ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Cancer ; Cell Biology ; Cell Cycle Analysis ; Cell death ; DNA methylation ; Electron transport chain ; Hypoxia ; Hypoxia-inducible factor 1 ; Hypoxia-inducible factor 1a ; Life Sciences ; Localization ; Medical prognosis ; Medulloblastoma ; Metabolism ; Metastases ; Metformin ; NADH-ubiquinone oxidoreductase ; Post-translation ; Stem Cells ; Toxicity ; Tumors</subject><ispartof>Cell death discovery, 2024-07, Vol.10 (1), p.338-12, Article 338</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. 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><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c412t-26155792a525904d4f6336a1aaaa6312d463009ff86af5ac267bf5b42281939f3</cites><orcidid>0000-0002-5983-3782 ; 0000-0001-9333-4162 ; 0009-0007-8775-1614 ; 0000-0003-1350-7161</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269614/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269614/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39048564$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04760577$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Contenti, J.</creatorcontrib><creatorcontrib>Guo, Y.</creatorcontrib><creatorcontrib>Larcher, M.</creatorcontrib><creatorcontrib>Mirabal-Ortega, L.</creatorcontrib><creatorcontrib>Rouleau, M.</creatorcontrib><creatorcontrib>Irondelle, M.</creatorcontrib><creatorcontrib>Tiroille, V.</creatorcontrib><creatorcontrib>Mazzu, A.</creatorcontrib><creatorcontrib>Duranton-Tanneur, V.</creatorcontrib><creatorcontrib>Pedeutour, F.</creatorcontrib><creatorcontrib>Ben-Sahra, I.</creatorcontrib><creatorcontrib>Lago, C.</creatorcontrib><creatorcontrib>Leva, G.</creatorcontrib><creatorcontrib>Tiberi, L.</creatorcontrib><creatorcontrib>Robert, G.</creatorcontrib><creatorcontrib>Pouponnot, C.</creatorcontrib><creatorcontrib>Bost, F.</creatorcontrib><creatorcontrib>Mazure, N. M.</creatorcontrib><title>HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma</title><title>Cell death discovery</title><addtitle>Cell Death Discov</addtitle><addtitle>Cell Death Discov</addtitle><description>Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2’s transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. 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M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma</atitle><jtitle>Cell death discovery</jtitle><stitle>Cell Death Discov</stitle><addtitle>Cell Death Discov</addtitle><date>2024-07-24</date><risdate>2024</risdate><volume>10</volume><issue>1</issue><spage>338</spage><epage>12</epage><pages>338-12</pages><artnum>338</artnum><issn>2058-7716</issn><eissn>2058-7716</eissn><abstract>Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2’s transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. 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subjects | 631/154/53/2423 631/443/319/320 631/67/1857 631/67/2332 631/80/82/23 Apoptosis Biochemistry Biomedical and Life Sciences Cancer Cell Biology Cell Cycle Analysis Cell death DNA methylation Electron transport chain Hypoxia Hypoxia-inducible factor 1 Hypoxia-inducible factor 1a Life Sciences Localization Medical prognosis Medulloblastoma Metabolism Metastases Metformin NADH-ubiquinone oxidoreductase Post-translation Stem Cells Toxicity Tumors |
title | HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma |
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