α-Ketoglutarate links p53 to cell fate during tumour suppression

John P. Morris, Jossie J. Yashinskie, Richard Koche, Rohit Chandwani, Sha Tian, Chi Chao Chen, Timour Baslan, Zoran S. Marinkovic, Francisco J. Sánchez-Rivera, Steven D. Leach, Carlos Carmona Fontaine, Craig B. Thompson, Lydia W.S. Finley, Scott W. Lowe

Research output: Contribution to journalArticle

Abstract

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 development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, 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.

Original languageEnglish (US)
Pages (from-to)595-599
Number of pages5
JournalNature
Volume573
Issue number7775
DOIs
StatePublished - Sep 1 2019

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Neoplasms
Chromatin
Cell Differentiation
Adenocarcinoma
Ketoglutarate Dehydrogenase Complex
Gene Expression
Dioxygenases
Citric Acid Cycle
Succinic Acid
Enzymes
Mutation
5-hydroxymethylcytosine

ASJC Scopus subject areas

  • General

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Morris, J. P., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C. C., ... Lowe, S. W. (2019). α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature, 573(7775), 595-599. https://doi.org/10.1038/s41586-019-1577-5

α-Ketoglutarate links p53 to cell fate during tumour suppression. / Morris, John P.; Yashinskie, Jossie J.; Koche, Richard; Chandwani, Rohit; Tian, Sha; Chen, Chi Chao; Baslan, Timour; Marinkovic, Zoran S.; Sánchez-Rivera, Francisco J.; Leach, Steven D.; Carmona Fontaine, Carlos; Thompson, Craig B.; Finley, Lydia W.S.; Lowe, Scott W.

In: Nature, Vol. 573, No. 7775, 01.09.2019, p. 595-599.

Research output: Contribution to journalArticle

Morris, JP, Yashinskie, JJ, Koche, R, Chandwani, R, Tian, S, Chen, CC, Baslan, T, Marinkovic, ZS, Sánchez-Rivera, FJ, Leach, SD, Carmona Fontaine, C, Thompson, CB, Finley, LWS & Lowe, SW 2019, 'α-Ketoglutarate links p53 to cell fate during tumour suppression', Nature, vol. 573, no. 7775, pp. 595-599. https://doi.org/10.1038/s41586-019-1577-5
Morris JP, Yashinskie JJ, Koche R, Chandwani R, Tian S, Chen CC et al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature. 2019 Sep 1;573(7775):595-599. https://doi.org/10.1038/s41586-019-1577-5
Morris, John P. ; Yashinskie, Jossie J. ; Koche, Richard ; Chandwani, Rohit ; Tian, Sha ; Chen, Chi Chao ; Baslan, Timour ; Marinkovic, Zoran S. ; Sánchez-Rivera, Francisco J. ; Leach, Steven D. ; Carmona Fontaine, Carlos ; Thompson, Craig B. ; Finley, Lydia W.S. ; Lowe, Scott W. / α-Ketoglutarate links p53 to cell fate during tumour suppression. In: Nature. 2019 ; Vol. 573, No. 7775. pp. 595-599.
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