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.

Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia

“…This gene codes for a protein that is involved in the catabolism of branched-chain amino acids. 33 Aberrations in this gene have not been previously reported in ALL, but up-regulation of BCAT1 has been implicated in gliomas and nasopharyngeal carcinoma. 33,34 However, the deletions seen in our study would rather be expected to result in underexpression of BCAT1.…”

“…33 Aberrations in this gene have not been previously reported in ALL, but up-regulation of BCAT1 has been implicated in gliomas and nasopharyngeal carcinoma. 33,34 However, the deletions seen in our study would rather be expected to result in underexpression of BCAT1. PIK3AP1 (10q24.1), found deleted in 2% of our cases, has previously been reported to be deleted in a single case of adult ALL.…”

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

“…This autosomal recessive neurometabolic disorder results in the accumulation of 2HG isomers (51,52). These compounds are metabolic intermediates in reactions catalyzed by malate dehydrogenase and hydroxyacid-oxoacid transhydrogenase (53,54), and accumulation of 2HG affects some metabolic processes, such as the TCA cycle and branched-chain amino acid metabolism (55,56). It is characterized by elevated urinary levels of Krebs' cycle intermediates and neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development, resulting in early death (1 month to up to 5 years in age; summarized in Ref.…”

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

“…In adult mammals, BCATc expression is limited to the nervous system and gonadal tissues; however, BCATc is expressed in proliferating cells of embryonic or cancer origin (8, 24 -26). BCATc is thought to be a potential diagnostic marker for aggressive IDH wt glioblastomas (25). In this study, we examined the biochemical and metabolic consequences of changes in BCATc expression during TCR-induced activation in CD4 ϩ T cells.…”