Alpha-ketoglutarate links p53 to cell fate during tumor suppression
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ABSTRACT:
PROVIDER: PRJNA471027 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7152872_1.fastq.gz | Fastqsanger.gz | |||
| SRR7152872_2.fastq.gz | Fastqsanger.gz | |||
| SRR7152873_1.fastq.gz | Fastqsanger.gz | |||
| SRR7152873_2.fastq.gz | Fastqsanger.gz | |||
| SRR7152874_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:The tumor suppressor p53 is mutated in the majority of human cancers, including pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress and acts to regulate the expression of genes that influence cell fate and constrain tumorigenesis2. p53 also can modulate cellular metabolism3, though it remains unclear how the metabolic effects of p53 influence tumor suppression or whether the metabolic consequences of p53 loss play a role in disease maintenance. Here, we show that restoring endogenous p53 function in cancer cells derived from a mouse model of PDAC driven by oncogenic Kras and a regulatable p53 short hairpin RNA (shRNA) rewires glucose and glutamine metabolism to support the accumulation of the metabolite alpha-ketoglutarate, an obligate substrate for several enzymes that regulate chromatin methylation. p53 restoration induces transcriptional programs characteristic of pre-neoplastic differentiation, an effect that can be partially recapitulated by addition of cell permeable alpha-ketoglutarate. Consequently, enforcing alpha-ketoglutarate accumulation in p53 deficient cells by inhibiting expression of oxoglutarate dehydrogenase (Ogdh), the enzyme that consumes alpha-ketoglutarate in the tricarboxylic acid cycle, reduces tumor-initiating capacity and promotes tumor differentiation in vivo. In both mouse and human pancreatic cancer, decreasing levels of the alpha-ketoglutarate-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) marks progression from prenoplastic to de-differentiated malignant lesions. p53 restoration or Ogdh suppression promotes accumulation of 5hmC specifically in differentiated tumor cells in vivo. Together, these results nominate alpha-ketoglutarate as an effector of p53-mediated tumor suppression that promotes pre-neoplastic differentiation and suppresses malignant progression.
2019-09-09 | GSE114263 | GEO
Project description:Alpha-ketoglutarate links p53 to cell fate during tumor suppression
| PRJNA470700 | ENA
Project 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 α-ketoglutarate (αKG), 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 αKG. Similarly, enforcing αKG accumulation in p53-deficient PDAC cells though the inhibition of oxoglutarate (αKG) dehydrogenase (Ogdh), the enzyme that consumes αKG in the tricarboxylic acid cycle, reduces tumor-initiating capacity and promotes tumor cell differentiation. Decreases in 5-hydroxymethylcytosine (5hmC), an αKG-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 αKG as an effector of p53-mediated tumor suppression whose accumulation in p53-deficient tumors can drive tumor cell differentiation and antagonize malignant progression.
2019-05-10 | GSE114342 | GEO
Project description: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.
| S-EPMC6830448 | biostudies-literature
Project description:p53 prevents tumor initiation and progression by adapting cell fate via transcriptional regulation of target gene networks. Here, we find that cancer associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes outgrowth of cancer cells with transcriptionally active, wild type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG) dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression. Mutant IDH interferes with the expression of pro-apoptotic p53 targets, including the death ligand receptor Fas that enables p53 dependent liver tumor regressions. Pharmacological inhibition of mutant IDH in TP53 wildtype cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy induced apoptosis. Therefore, we implicate disruption of p53 target gene regulation as a reversable, oncogenic feature of cancer associated IDH mutations.
2025-04-30 | GSE279597 | GEO
Project description:p53 prevents tumor initiation and progression by adapting cell fate via transcriptional regulation of target gene networks. Here, we find that cancer associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes outgrowth of cancer cells with transcriptionally active, wild type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG) dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression. Mutant IDH interferes with the expression of pro-apoptotic p53 targets, including the death ligand receptor Fas that enables p53 dependent liver tumor regressions. Pharmacological inhibition of mutant IDH in TP53 wildtype cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy induced apoptosis. Therefore, we implicate disruption of p53 target gene regulation as a reversable, oncogenic feature of cancer associated IDH mutations.
2025-04-30 | GSE279555 | GEO
Project description:Transcriptome analysis following Dimethyl α-Ketoglutarate treatment
2025-03-19 | GSE279001 | GEO
Project description:EDC4 C-terminal domain scaffolds P-body assembly and links P-body dynamics to p53 mediated tumor suppression
| PRJNA1164755 | ENA
Project description:Tet3 is an Fe2+-dependent enzyme that oxidizes genomic 5-methylcytosine to 5-hydroxymethylcytosine with the help of alpha-ketoglutarate and oxygen. It is the most abundant Tet enzyme in differentiated tissues including brain. Adult brain contains the highest 5-hydroxymethylcytosine levels. How alpha-ketoglutarate is made available for the oxidation of mC in brain cells and how the Tet activity is linked to neural activity are unsolved questions. Our experiments with full mouse brains show that Tet3 interacts in the nucleus directly with selected enzymes of the mitochondrial citric acid cycle. This leads to the formation of isocitrate. Tet3 also interacts with aspartate aminotransferase, which produces oxaloacetate. Although oxaloacetate and isocitrate are biosynthetic alpha-ketoglutarate precursors, they function as inhibitors of Tet3 and are needed to protect the reactive Fe2+ center from degrading DNA. The supply of Tet3 with alpha-ketoglutarate is established by a direct interaction of Tet3 with glutamate dehydrogenase (Glud1), which converts the neurotransmitter glutamate directly into alpha-ketoglutarate. This links Tet3 function to neural activity.
2021-05-10 | PXD004518 | Pride
Project description:The role of p53 in pancreatic cancer suppression
| PRJNA932333 | ENA