α-Ketoglutarate links p53 to cell fate during tumour suppression

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 alpha-ketoglutarate (alpha KG, 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 alpha KG. Increased levels of the alpha KG-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 alpha KG 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 alpha KG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that alpha KG is an effector of p53-mediated tumour suppression, and that the accumulation of alpha KG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.