title: Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition.
abstract: Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-β-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-β signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.
authors.affiliation: Departments of Gastrointestinal Surgery and Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hamabe
authors.affiliation: Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Konno
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Sendai 981-1293, Japan;
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanuma
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Sendai 981-1293, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.affiliation: Taiho Pharmaceutical Co., Ltd., Chiyoda-ku, Tokyo 101-0054, Japan; Taiho Pharmaceutical Co., Ltd., Chiyoda-ku, Tokyo 101-0054, Japan; Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Kenta
authors.initials: K
authors.lastname: Tsunekuni
authors.affiliation: Departments of Gastrointestinal Surgery and Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Jun
authors.initials: J
authors.lastname: Koseki
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan; and.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Departments of Gastrointestinal Surgery and.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Departments of Gastrointestinal Surgery and Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Departments of Gastrointestinal Surgery and Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; mmori@gesurg.med.osaka-u.ac.jp hishii@gesurg.med.osaka-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; mmori@gesurg.med.osaka-u.ac.jp hishii@gesurg.med.osaka-u.ac.jp.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D011770:Pyruvate Kinase / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D004265:DNA Helicases; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D011770:Pyruvate Kinase; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C414585:TGIF2 protein, human; C080359:CHD1 protein, human
keywords: colorectal cancer; epithelial–mesenchymal transition; invasion; pyruvate kinase M2; transforming growth factor-β–induced factor homeobox 2