α-Ketoglutarate links p53 to cell fate during tumour suppression
Open accessAbstract
The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development 2. Wild-type p53 is also known to modulate cellular metabolic pathways 3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase-an enzyme of the tricarboxylic acid cycle-specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
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Altered p53 function has multiple tumor-promoting effects on neoplastic cells, including increased genomic instability, reprogrammed cellular metabolism, and enhanced metastatic propensity.
“altered p53 function has a multitude of tumor-promoting effects on neoplastic cells, including increased genomic instability30, reprogrammed cellular metabolism57,58, and enhanced metastatic propensity59.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [57]
In cell lines from mouse models of pancreatic ductal adenocarcinoma driven by mutant Kras and reversible silencing of p53, restoring p53 function rewires TCA cycle metabolism and drives accumulation of αKG relative to succinate.
“In cell lines derived from mouse models of pancreatic ductal adenocarcinoma driven by mutant Kras and reversible silencing of the tumor suppressor p53, restoring p53 function rewires TCA cycle metabolism and drives accumulation of αKG relative to succinate (164).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [164]
An increased αKG/succinate ratio in this system, whether driven by p53 reactivation or suppression of OGDH, enhances activity of αKG-dependent dioxygenases like the TETs and drives reacquisition of premalignant gene expression patterns associated with tumor differentiation.
“An increased αKG/succinate ratio in this system, whether driven by p53 reactivation or suppression of OGDH, enhances activity of αKG-dependent dioxygenases like the TETs and drives reacquisition of premalignant gene expression patterns associated with tumor differentiation (164).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [164]
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References 62 · Cited by 296
- Authors
- Morris, J. P., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C.-C., Baslan, T., Marinkovic, Z. S., Sánchez-Rivera, F. J., Leach, S. D., Carmona-Fontaine, C., Thompson, C. B., Finley, L. W. S., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- New York University (US)
- Dartmouth College (US)
- Corresponding author
- Finley, Lydia W. S.
- Lowe, Scott W.
- ORCID
- Venue
- Nature
- Published
- 2019-09-18
- Volume
- 573
- Issue
- 7775
- Pages
- 595-599
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6830448
- OpenAlex
- W2973444726
- Cited by
- 296
- References
- 62
- Citations by year
- 2026: 31 · 2025: 40 · 2024: 46 · 2023: 45 · 2022: 49 · 2021: 46 · 2020: 34 · 2019: 5
- FWCI
- 14.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (T32CA160001, P01CA087497, R00CA191021, R01CA204228, P01CA013106, P30CA008748)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD060600)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- p53, alpha-ketoglutarate, pancreatic ductal adenocarcinoma, tumor suppression, 5-hydroxymethylcytosine, cell differentiation, cancer metabolism, 2-oxoglutarate dehydrogenase, succinic acid, chromatin modification, KRAS mutation, precancerous lesions
- MeSH terms
- Animals, Cell Differentiation, Disease Models, Animal, Ketoglutaric Acids, Pancreatic Neoplasms, Protein Binding, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Succinic Acid, Carcinoma, Pancreatic Ductal, Chromatin Assembly and Disassembly, Cell Line, Tumor, Mice
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