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.
Bibliographical noteFunding Information:
We thank G. Tödt for bioinformatic expertise, M. Kirchgäßner, K. Pfleger, E. Wieland, A.-C. Klein, S. Emmerich and the DKFZ Light Microscopy Facility for excellent technical support, C. Schmidt (DKFZ) for providing the HEY1-pDest-vectors and A. von Deimling (University of Heidelberg) for providing the IDH1-specific antibodies. This work was supported by the German Federal Ministry of Education and Research (BMBF) within the National Genome Research Network NGFNplus (01GS0883 and 01GS0884) to B.R., P.L. and G.R., the German Cancer Aid (Deutsche Krebshilfe, grant number 108456) to B.R. and P.L. and the intramural funding program of the National Tumor Center Heidelberg. Y.J.P. was supported by the Roman Herzog research fellowship from the Hertie Foundation, Germany, and the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120071-1211-0000200).