ArticleNature metabolism2022
Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate.
Article in Nature metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Metabolites as signalling molecules in the tumour immune microenvironment.Nature reviews. Immunology · 2026Review
- Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis.Cell reports. Medicine · 2026Article
- Mutant p53 Regulates Pyruvate Dehydrogenase Kinase 1 (PDK1) to Promote Proliferation and Migration in Breast Cancer.Cancer science · 2026Article
- CYP4F11 promotes lung cancer progression through the miR-195/ME2 pathway.Frontiers of medicine · 2025Article
- Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.Molecular cancer · 2025Review
- Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Mutant p53 Gain of Function: Why Many See It, Why Some Do Not.Cancer discovery · 2025Article
- Discovery of Drugs Targeting Mutant p53 and Progress in Nano-Enabled Therapeutic Strategy for p53-Mutated Cancers.Biomolecules · 2025Review
- Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.Nature microbiology · 2025Article
- ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Metabolic regulation by p53: Implications for cancer therapy.Molecules and cells · 2025Review
- Malic enzymes in cancer: Regulatory mechanisms, functions, and therapeutic implications.Redox biology · 2024Review
- Homeostatic regulation of NAD(H) and NADP(H) in cells.Genes & diseases · 2024Review
- An Ultrasensitive Biosensor for Probing Subcellular Distribution and Mitochondrial Transport of l-2-Hydroxyglutarate.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- PKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer.The EMBO journal · 2024Article
- AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.Nature communications · 2024Article
- Altered Metabolism and Inflammation Driven by Post-translational Modifications in Intervertebral Disc Degeneration.Research (Washington, D.C.) · 2024Article
- SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration.Cell death and differentiation · 2024Article
- The Tricarboxylic Acid Cycle Metabolites for Cancer: Friend or Enemy.Research (Washington, D.C.) · 2024Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Many types of cancer feature TP53 mutations with oncogenic properties. However, whether the oncogenic activity of mutant p53 is affected by the cellular metabolic state is unknown. Here we show that cancer-associated mutant p53 protein is stabilized by 2-hydroxyglutarate generated by malic enzyme 2. Mechanistically, malic enzyme 2 promotes the production of 2-hydroxyglutarate by adjusting glutaminolysis, as well as through a reaction that requires pyruvate and NADPH. Malic enzyme 2 depletion decreases cellular 2-hydroxyglutarate levels in vitro and in vivo, whereas elevated malic enzyme 2 expression increases 2-hydroxyglutarate production. We further show that 2-hydroxyglutarate binds directly to mutant p53, which reduces Mdm2-mediated mutant p53 ubiquitination and degradation. 2-Hydroxyglutarate supplementation is sufficient for maintaining mutant p53 protein stability in malic enzyme 2-depleted cells, and restores tumour growth of malic enzyme 2-ablated cells, but not of cells that lack mutant p53. Our findings reveal the previously unrecognized versatility of malic enzyme 2 catalytic functions, and uncover a role for mutant p53 in sensing cellular 2-hydroxyglutarate levels, which contribute to the stabilization of mutant p53 and tumour growth.
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