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Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
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HIF1α/ATF3 partake in PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma
Shixue Yang1, Qi Zhan1, Dongyuan Su1
1Laboratory of Neuro-oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.
Neuro-Oncology
|March 5, 2024
Summary
This study reveals how HIF1α and ATF3 regulate P4HA1, impacting succinate levels and PGK1 succinylation in glioblastoma. This pathway influences aerobic glycolysis and tumor growth, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hypoxia is a key feature in glioblastoma (GBM) and other cancers.
- While hypoxic signaling and protein modifications are studied, the role of glycolytic enzyme PGK1 in tumorigenesis is unclear.
Purpose of the Study:
- To investigate the mechanisms by which PGK1 influences glioblastoma pathology.
- To explore the interplay between HIF1α, ATF3, P4HA1, and PGK1 succinylation in GBM.
Main Methods:
- ChIP assays to study HIF1α and ATF3 interactions with P4HA1.
- Protein degradation, LC-MS/MS, and in vitro assays to analyze succinylation.
- Seahorse assays to assess glucose metabolism.
- In vivo intracranial mouse models to evaluate ATF3 and P4HA1 impact.
Main Results:
- HIF1α and ATF3 differentially regulate P4HA1 transcription, affecting succinate production and HIF1α signaling.
- Elevated P4HA1 increases succinate, leading to PGK1 succinylation at K191/K192.
- PGK1 succinylation enhances aerobic glycolysis and lactate production.
- ATF3 overexpression and P4HA1 knockdown inhibit GBM growth and immune responses.
Conclusions:
- HIF1α/ATF3 and P4HA1/succinate signaling are critical regulators of succinate biosynthesis and PGK1 succinylation in GBM.
- The P4HA1/succinate pathway presents a potential therapeutic target for inhibiting aerobic glycolysis in GBM.
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