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An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline
Stephanie M Casillo1, Taylor A Gatesman1, Akanksha Chilukuri1
1Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Abstract:
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.
Insights
Pediatric diffuse midline glioma with H3K27M mutation shows altered metabolism. Targeting the ERK5-PFKFB3 pathway offers a promising therapeutic strategy for this aggressive brain tumor.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Pediatric diffuse midline glioma (DMG) is characterized by the H3K27M histone mutation.
- This mutation drives metabolic reprogramming and activates oncogenic signaling, including the RAS pathway.
- Extracellular-signal-related kinase 5 (ERK5) is a known critical mediator of tumor growth in DMG-H3K27a.
Purpose of the Study:
- To investigate downstream effectors of ERK5 in DMG-H3K27a metabolic reprogramming.
- To elucidate the role of ERK5 in regulating cell proliferation and glycolysis.
- To identify potential therapeutic targets within the ERK5 signaling axis.
Main Methods:
- In vitro and mouse models of diffuse midline glioma with altered H3K27 (DMG-H3K27a).
- Analysis of gene expression and protein modulation.
- Assessment of cell proliferation and glycolytic activity.
- Evaluation of therapeutic efficacy of targeting the ERK5-PFKFB3 axis.
Main Results:
- ERK5 was confirmed as a critical regulator of cell proliferation and glycolysis in DMG-H3K27a.
- ERK5 activates transcription factor MEF2A, which modulates the expression of glycolytic enzyme PFKFB3.
- DMG-H3K27a models demonstrated sensitivity to PFKFB3 loss.
Conclusions:
- The ERK5-MEF2A-PFKFB3 axis is a key pathway in DMG-H3K27a metabolic reprogramming.
- Targeting this axis, particularly PFKFB3, shows therapeutic potential.
- Multi-targeted drug therapy against the ERK5-PFKFB3 axis may offer a promising treatment strategy for pediatric diffuse midline glioma.
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