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Nat Med. 2013 Jul;19(7):901-908. doi: 10.1038/nm.3217. Epub 2013 Jun 23.

BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1.

Author information

1
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
3
Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University, Seoul, South Korea.
4
Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany.
5
Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
6
Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany.
7
Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.
8
Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute, Blacksburg, Virginia, USA.
9
Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany.
10
Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart, Germany.
11
Division of Experimental Neurosurgery, University of Heidelberg, Heidelberg, Germany.
12
Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
13
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
14
Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
15
Reutlingen University of Applied Science, Reutlingen, Germany.
16
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
17
Core Facility, Molecular Structural Analysis, DKFZ, Heidelberg, Germany.
18
Core Facility, Small Animal Imaging Center, DKFZ, Heidelberg, Germany.
19
German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany.
#
Contributed equally

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.

PMID:
23793099
PMCID:
PMC4916649
DOI:
10.1038/nm.3217
[Indexed for MEDLINE]
Free PMC Article

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