title: Nuclear pyruvate kinase M2 complex serves as a transcriptional coactivator of arylhydrocarbon receptor.
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.
authors.affiliation: Research Center for Environmental Quality Management, Kyoto University, Shiga 520-0811, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Laboratory of Proteome Research, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Adachi
authors.affiliation: Research Center for Environmental Quality Management, Kyoto University, Shiga 520-0811, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi 981-1293, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanuma
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi 981-1293, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka
authors.affiliation: Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Masae
authors.initials: M
authors.lastname: Ikura
authors.affiliation: Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.affiliation: Research Center for Environmental Quality Management, Kyoto University, Shiga 520-0811, Japan matsuda.tomonari.8z@kyoto-u.ac.jp.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000107:Acetylation; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins; D000099224:p300-CBP-Associated Factor
chemical_list: D001324:Autoantigens; D002352:Carrier Proteins; D002843:Chromatin; D019363:Cytochrome P-450 CYP1A1; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D006657:Histones; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018336:Receptors, Aryl Hydrocarbon; D013963:Thyroid Hormones; D050880:p300-CBP Transcription Factors; D000097810:Thyroid Hormone-Binding Proteins; D000099224:p300-CBP-Associated Factor; C569463:CYP1A1 protein, human; C052359:DLAT protein, human