Restoration of p53 led to an accumulation of αKG in mouse pancreatic cancer cells.
Major Finding: Restoration of p53 led to an accumulation of αKG in mouse pancreatic cancer cells.
Mechanism: p53- and αKG-triggered changes in chromatin accessibility and gene expression overlapped.
Impact: This work establishes a previously unknown metabolic link between p53 and αKG in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is often characterized by mutations affecting both KRAS and TP53. Oncogenic KRAS mutations have been demonstrated to have metabolic consequences in PDAC cells, but the potential effects of TP53 mutations on PDAC metabolism have not been established. Morris, Yashinskie, and colleagues found that the restoration of wild-type p53 in a mouse PDAC model in which p53 had previously been inactivated led to accumulation of citrate and α-ketoglutarate (αKG), while the levels of glutamine-oxidation metabolites (including succinate, malate, and aspartate) decreased, increasing the ratio of αKG to succinate. The mechanism behind this metabolic shift is unclear, but the results of further experiments implied that alterations in the levels of several enzymes of the tricarboxylic acid (TCA) cycle triggered by the transcriptional functions of p53 may be involved. Treatment of the same PDAC cells used in the mouse model with αKG or restoration of p53 function led to increases in chromatin accessibility, with a large degree of overlap between the regions made accessible by p53 reactivation and αKG administration. Expression of genes specifically expressed in cells from premalignant pancreatic intraepithelial neoplasias were increased by p53 and αKG, whereas expression of genes selectively expressed in PDAC cells was decreased, indicating a potential connection to pancreatic cancer progression. In the mouse model, inhibition of oxoglutarate dehydrogenase (the TCA-cycle enzyme that converts αKG to succinyl-coenzyme A) led to a phenotype similar to that caused by p53 restoration, with promotion of cell differentiation and tumor suppression. Additionally, p53 status and the ratio of αKG to succinate determined the level of 5hmC, produced by the strictly αKG-dependent ten–eleven translocation enzymes, in the mouse PDAC model. Collectively, this work defines a previously unknown connection between p53 and metabolism in PDAC; further, this study suggests that it may be worth investigating therapies that increase αKG levels in p53-deficient tumors.
Morris JP IV, Yashinskie JJ, Koche R, Chandwani R, Tian S, Chen CC, et al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature 2019;573:595–9.
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