α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99296 | GEO | 2017/07/03
SECONDARY ACCESSION(S): PRJNA388056
REPOSITORIES: GEO
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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:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140264 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140265 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140263 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
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Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140267 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140266 | GEO
Project description:The malate shuttle is traditionally known to maintain the NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions was unknown. Here we show that chronic viral infections induced the expression of GOT1, the key enzyme in the malate shuttle, in CD8+ T cells. Got1 deficiency indeed decreased the NAD+/NADH ratio and dampened antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore antiviral T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate and led to toxic ammonia accumulation in CD8+ T cells. Supplementation with 2-ketoglutarate assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. This study suggests that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH ratio, but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infections.
2023-09-01 | GSE220876 | GEO
Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.
2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress
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.
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