Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
Nat Med. 2013 Jul;19(7):901-908. doi: 10.1038/nm.3217. Epub 2013 Jun 23.
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.
在这里，我们表明胶质母细胞瘤表达高水平的支链氨基酸转氨酶 1（BCAT1），该酶启动支链氨基酸（BCAAs）的分解代谢。BCAT1 的表达仅限于携带野生型异柠檬酸脱氢酶 1（IDH1）和 IDH2 基因的肿瘤，并且与 BCAT1 启动子区域的甲基化模式高度相关。BCAT1 的表达依赖于胶质瘤细胞系中 α-酮戊二酸底物的浓度，并且可以通过在永生化的人星形胶质细胞中异位过表达突变型 IDH1 来抑制，为 IDH1 功能与 BCAT1 表达之间提供了联系。在胶质瘤细胞系中抑制 BCAT1 可阻断谷氨酸的排泄，并导致体外增殖和侵袭性降低，以及胶质母细胞瘤异种移植模型中的肿瘤生长显著减少。这些发现表明 BCAT1 在神经胶质瘤发病机制中起核心作用，使 BCAT1 和支链氨基酸代谢成为开发针对治疗胶质母细胞瘤患者的靶向治疗方法的有吸引力的目标。
