Branched-chain amino acid transaminase 1 (BCAT1) drives growth of gliomas with wild-type IDH1.

  • Major finding: Branched-chain amino acid transaminase 1 (BCAT1) drives growth of gliomas with wild-type IDH1.

  • Mechanism: Mutant IDH1 downregulates BCAT1 in association with altered BCAT1 promoter methylation.

  • Impact: Targeting branched-chain amino acid metabolism in gliomas may be an effective therapeutic strategy.

Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are frequently found in high-grade gliomas and secondary glioblastomas that develop from low-grade gliomas but are rare in primary glioblastomas. Mutant IDH enzymes are believed to metabolically reprogram cancer cells through the neomorphic conversion of to α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), but the metabolic conditions that support the aggressive growth of IDH–wild-type gliomas are less clear. Tönjes and colleagues found that expression of branched-chain amino acid transaminase 1 (BCAT1) was significantly higher in gliomas lacking mutations in IDH1 or IDH2 than in IDH-mutant gliomas, where BCAT1 was essentially absent. In the initial step of branched-chain amino acid catabolism, glutamate and branched-chain α-ketoacids are generated by BCATs through the transfer of an α-amino group to α-KG, suggesting a potential link to the activity of wild-type IDH enzymes, which convert isocitrate to α-KG, as well as to release of glutamate by glioblastoma cells, which facilitates tumor expansion by inducing the excitotoxic cell death of surrounding neurons. Indeed, BCAT1 expression was strongly downregulated upon IDH1 knockdown or overexpression of mutant IDH1 and could be rescued by α-KG, not 2-HG. Furthermore, consistent with the known ability of 2-HG to inhibit the activity of α-KG–dependent enzymes such as 5-methylcytosine hydroxylases, altered BCAT1 promoter DNA methylation in IDH-mutant gliomas was strongly correlated with BCAT1 downregulation. BCAT1 knockdown or inhibition with a leucine analogue also markedly reduced the proliferation, migration, invasion, and glutamate release of glioblastoma cells in vitro, and BCAT1 knockdown significantly blocked tumor growth and glutamate excretion in vivo. These findings indicating that IDH1–wild-type gliomas are addicted to BCAT1-dependent branched-chain amino acid catabolism thus suggest that selectively targeting this process may have therapeutic benefit

Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 2013;19:901–8.

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