An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma
Copyright © 2023. Published by Elsevier Inc..
Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Cell reports - 43(2024), 1 vom: 23. Jan., Seite 113557 |
| Sprache: |
Englisch |
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| Links: |
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| Anmerkungen: |
Date Completed 05.02.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2023.113557 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM366038354 |
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| 100 | 1 | |a Casillo, Stephanie M |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 05.02.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023. Published by Elsevier Inc. | ||
| 520 | |a Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a CP: Cancer | |
| 650 | 4 | |a CP: Metabolism | |
| 650 | 4 | |a ERK5 | |
| 650 | 4 | |a H3K27a-DMG | |
| 650 | 4 | |a MEF2A | |
| 650 | 4 | |a PFKFB3 | |
| 650 | 4 | |a glioma | |
| 650 | 4 | |a glycolysis | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a multi targeted | |
| 650 | 4 | |a pediatric | |
| 650 | 4 | |a synergy | |
| 650 | 7 | |a Extracellular Signal-Regulated MAP Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Histones |2 NLM | |
| 650 | 7 | |a PFKFB3 protein, human |2 NLM | |
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| 650 | 7 | |a Phosphofructokinase-2 |2 NLM | |
| 650 | 7 | |a EC 2.7.1.105 |2 NLM | |
| 650 | 7 | |a Phosphoric Monoester Hydrolases |2 NLM | |
| 650 | 7 | |a EC 3.1.3.2 |2 NLM | |
| 650 | 7 | |a MAPK7 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 700 | 1 | |a Gatesman, Taylor A |e verfasserin |4 aut | |
| 700 | 1 | |a Chilukuri, Akanksha |e verfasserin |4 aut | |
| 700 | 1 | |a Varadharajan, Srinidhi |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Brenden J |e verfasserin |4 aut | |
| 700 | 1 | |a David Premkumar, Daniel R |e verfasserin |4 aut | |
| 700 | 1 | |a Jane, Esther P |e verfasserin |4 aut | |
| 700 | 1 | |a Plute, Tritan J |e verfasserin |4 aut | |
| 700 | 1 | |a Koncar, Robert F |e verfasserin |4 aut | |
| 700 | 1 | |a Stanton, Ann-Catherine J |e verfasserin |4 aut | |
| 700 | 1 | |a Biagi-Junior, Carlos A O |e verfasserin |4 aut | |
| 700 | 1 | |a Barber, Callie S |e verfasserin |4 aut | |
| 700 | 1 | |a Halbert, Matthew E |e verfasserin |4 aut | |
| 700 | 1 | |a Golbourn, Brian J |e verfasserin |4 aut | |
| 700 | 1 | |a Halligan, Katharine |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Andrea F |e verfasserin |4 aut | |
| 700 | 1 | |a Mansi, Neveen M |e verfasserin |4 aut | |
| 700 | 1 | |a Cheney, Allison |e verfasserin |4 aut | |
| 700 | 1 | |a Mullett, Steven J |e verfasserin |4 aut | |
| 700 | 1 | |a Land, Clinton Van't |e verfasserin |4 aut | |
| 700 | 1 | |a Perez, Jennifer L |e verfasserin |4 aut | |
| 700 | 1 | |a Myers, Max I |e verfasserin |4 aut | |
| 700 | 1 | |a Agrawal, Nishant |e verfasserin |4 aut | |
| 700 | 1 | |a Michel, Joshua J |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Yue-Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Vaske, Olena M |e verfasserin |4 aut | |
| 700 | 1 | |a MichaelRaj, Antony |e verfasserin |4 aut | |
| 700 | 1 | |a Lieberman, Frank S |e verfasserin |4 aut | |
| 700 | 1 | |a Felker, James |e verfasserin |4 aut | |
| 700 | 1 | |a Shiva, Sruti |e verfasserin |4 aut | |
| 700 | 1 | |a Bertrand, Kelsey C |e verfasserin |4 aut | |
| 700 | 1 | |a Amankulor, Nduka |e verfasserin |4 aut | |
| 700 | 1 | |a Hadjipanayis, Costas G |e verfasserin |4 aut | |
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| 700 | 1 | |a Zinn, Pascal O |e verfasserin |4 aut | |
| 700 | 1 | |a Friedlander, Robert M |e verfasserin |4 aut | |
| 700 | 1 | |a Abel, Taylor J |e verfasserin |4 aut | |
| 700 | 1 | |a Nazarian, Javad |e verfasserin |4 aut | |
| 700 | 1 | |a Venneti, Sriram |e verfasserin |4 aut | |
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| 700 | 1 | |a Agnihotri, Sameer |e verfasserin |4 aut | |
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