title: BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1.
abstract: Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martje
authors.initials: M
authors.lastname: Tönjes
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Barbus
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.|Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University, Seoul, South Korea.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Schlotter
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Lindroth
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany.
authors.forename: Sabrina V
authors.initials: SV
authors.lastname: Pleier
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Alfa H C
authors.initials: AHC
authors.lastname: Bai
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Karra
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany.|Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.
authors.forename: Rosario M
authors.initials: RM
authors.lastname: Piro
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute, Blacksburg, Virginia, USA.
authors.forename: Adele
authors.initials: A
authors.lastname: Addington
authors.affiliation: Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lemke
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Weibrecht
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart, Germany.
authors.forename: Claudio G
authors.initials: CG
authors.lastname: Rolli
authors.affiliation: Division of Experimental Neurosurgery, University of Heidelberg, Heidelberg, Germany.|Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benito
authors.initials: B
authors.lastname: Campos
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Division of Experimental Neurosurgery, University of Heidelberg, Heidelberg, Germany.|Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart, Germany.|Reutlingen University of Applied Science, Reutlingen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kemkemer
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany.|Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Core Facility, Molecular Structural Analysis, DKFZ, Heidelberg, Germany.
authors.forename: William-Edmund
authors.initials: WE
authors.lastname: Hull
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Core Facility, Small Animal Imaging Center, DKFZ, Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute, Blacksburg, Virginia, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hutson
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.|German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000502:physiology; D008660:Metabolism / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D000637:Transaminases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000597:Amino Acids, Branched-Chain; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C490590:BCAT1 protein, human; D000637:Transaminases