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 () and Scott W. Lowe ()
Additional contact information
John P. Morris: Memorial Sloan Kettering Cancer Center
Jossie J. Yashinskie: Memorial Sloan Kettering Cancer Center
Richard Koche: Memorial Sloan Kettering Cancer Center
Rohit Chandwani: Weill Cornell Medical College
Sha Tian: Memorial Sloan Kettering Cancer Center
Chi-Chao Chen: Memorial Sloan Kettering Cancer Center
Timour Baslan: Memorial Sloan Kettering Cancer Center
Zoran S. Marinkovic: New York University
Francisco J. Sánchez-Rivera: Memorial Sloan Kettering Cancer Center
Steven D. Leach: Memorial Sloan Kettering Cancer Center
Carlos Carmona-Fontaine: New York University
Craig B. Thompson: Memorial Sloan Kettering Cancer Center
Lydia W. S. Finley: Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Memorial Sloan Kettering Cancer Center

Nature, 2019, vol. 573, issue 7775, 595-599

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1577-5

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