Abstract
Pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase complex (PDC) regulate production of acetyl-CoA, which functions as an acetyl donor in diverse enzymatic reactions, including histone acetylation. However, the mechanism by which the acetyl-CoA required for histone acetylation is ensured in a gene context-dependent manner is not clear. Here we show that PKM2, the E2 subunit of PDC and histone acetyltransferase p300 constitute a complex on chromatin with arylhydrocarbon receptor (AhR), a transcription factor associated with xenobiotic metabolism. All of these factors are recruited to the enhancer of AhR-target genes, in an AhR-dependent manner. PKM2 contributes to enhancement of transcription of cytochrome P450 1A1 (CYP1A1), an AhR-target gene, acetylation at lysine 9 of histone H3 at the CYP1A1 enhancer. Site-directed mutagenesis of PKM2 indicates that this enhancement of histone acetylation requires the pyruvate kinase activity of the enzyme. Furthermore, we reveal that PDC activity is present in nuclei. Based on these findings, we propose a local acetyl-CoA production system in which PKM2 and PDC locally supply acetyl-CoA to p300 from abundant PEP for histone acetylation at the gene enhancer, and our data suggest that PKM2 sensitizes AhR-mediated detoxification in actively proliferating cells such as cancer and fetal cells.
Highlights
Acetyl-CoA is a central metabolite straddling diverse metabolic pathways, including glycolysis, the citric acid cycle, fatty acid oxidation, lipid biosynthesis, ketogenesis and amino acid metabolism
Pyruvate kinase M2 (PKM2), pyruvate dehydrogenase complex (PDC)-E2 and p300 constitute a complex with arylhydrocarbon receptor (AhR) on chromatin
We detected PKM2 and PDC-E2 in immuniprecipitate using anti-AhR antibody from the chromatin fraction of HeLa S3 cells (Figure 1C) and AhR and PKM2 in immuniprecipitate using anti-PDC-E2 antibody (Figure 1D). These findings indicate that PKM2, PDC-E2, p300 and AhR constitute a complex on chromatin
Summary
Acetyl-CoA is a central metabolite straddling diverse metabolic pathways, including glycolysis, the citric acid cycle, fatty acid oxidation, lipid biosynthesis, ketogenesis and amino acid metabolism. It participates in signal transduction as an acetyl donor for protein acetylation. Pyruvate kinase and pyruvate dehydrogenase complex (PDC) regulate a large portion of acetyl-CoA production from glucose intermediates. PDC is a mitochondrial protein complex which irreversibly decarboxylates pyruvate to produce acetyl-CoA, connecting glycolysis and the citric acid cycle. It has been reported that PKM2 enhances transcriptional activity via its protein kinase activity, for example through phosphorylation of Tyr705 of STAT3 [5] or Thr of histone H3 [9]. Whether or how these enzymes orchestrate transcriptional activation is still unknown
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