github link
Accession IconSRP145452

Alpha-ketoglutarate links p53 to cell fate during tumor suppression

Organism Icon Mus musculus
Sample Icon 6 Downloadable Samples
Technology Badge IconIllumina HiSeq 2500

Submitter Supplied Information

Description
The tumor suppressor TP53 is mutated in the majority of human cancers, including over 70% of pancreatic ductal adenocarcinoma (PDAC). Wild-type p53 accumulates in response to cellular stress and regulates the expression of genes that alter cell fate and constrain tumorigenesis. p53 also modulates several cellular metabolic pathways, though it remains unclear whether particular p53-regulated metabolites contribute to tumor suppression or whether metabolic alterations driven by p53 mutation sustain cancer progression. Here, we show that restoring endogenous p53 function in cancer cells derived from a murine PDAC model driven by oncogenic Kras and a regulatable p53 short hairpin RNA (shRNA) rewires glucose and glutamine metabolism leading to the accumulation of a-ketoglutarate (aKG), an obligate substrate for several chromatin modifying enzymes. p53 induces transcriptional programs characteristic of premalignant differentiation, an effect that can be partially recapitulated by addition of cell permeable aKG. Similarly, enforcing aKG accumulation in p53-deficient PDAC cells though the inhibition of oxoglutarate (aKG) dehydrogenase (Ogdh), the enzyme that consumes aKG in the tricarboxylic acid cycle, reduces tumor-initiating capacity and promotes tumor cell differentiation. Decreases in 5-hydroxymethylcytosine (5hmC), an aKG-dependent chromatin modification, are associated with the appearance of p53 mutations in the transition from premalignant to de-differentiated malignant lesions, whereas increases in 5hmC accompany tumor cell differentiation triggered by either p53 restoration or Ogdh depletion. Together these data nominate aKG as an effector of p53-mediated tumor suppression whose accumulation in p53-deficient tumors can drive tumor cell differentiation and antagonize malignant progression. Overall design: 6 samples were analyzed in duplicates of 3 conditions. 1. Control, KPsh cells grown on dox, treated with vehicle DMSO for 72 hours. 2. KPsh cells grown on dox, treated with 4mM cell permeable dimethyl-alpha ketoglutarate for 72 hours. 3. KPsh cells grown off dox for 8 days, treated with DMSO vehicle for 72 hours.
PubMed ID
Total Samples
6
Submitter’s Institution
No associated institution

Samples

Show of 0 Total Samples
Filter
Add/Remove
Accession Code
Title
Cell line
Treatment
Subject
Processing Information
Additional Metadata
No rows found
Loading...