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Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma

缺氧诱导因子对胶质母细胞瘤支链氨基酸代谢的调控

  • 影响因子:6.50
  • DOI:10.1007/s00018-020-03483-1
  • 作者列表:"Zhang, Bo","Chen, Yan","Shi, Xiaolei","Zhou, Mi","Bao, Lei","Hatanpaa, Kimmo J.","Patel, Toral","DeBerardinis, Ralph J.","Wang, Yingfei","Luo, Weibo
  • 发表时间:2020-02-22
Abstract

Hypoxia-inducible factors (HIFs) mediate metabolic reprogramming in response to hypoxia. However, the role of HIFs in branched-chain amino acid (BCAA) metabolism remains unknown. Here we show that hypoxia upregulates mRNA and protein levels of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1, but not their paralogs LAT2-4 and BCAT2, in human glioblastoma (GBM) cell lines as well as primary GBM cells. Hypoxia-induced LAT1 protein upregulation is mediated by both HIF-1 and HIF-2 in GBM cells. Although both HIF-1α and HIF-2α directly bind to the hypoxia response element at the first intron of the human BCAT1 gene, HIF-1α is exclusively responsible for hypoxia-induced BCAT1 expression in GBM cells. Knockout of HIF-1α and HIF-2α significantly reduces glutamate labeling from BCAAs in GBM cells under hypoxia, which provides functional evidence for HIF-mediated reprogramming of BCAA metabolism. Genetic or pharmacological inhibition of BCAT1 inhibits GBM cell growth under hypoxia. Together, these findings uncover a previously unrecognized HIF-dependent metabolic pathway that increases GBM cell growth under conditions of hypoxic stress.

摘要

缺氧诱导因子 (HIFs) 介导代谢重编程对缺氧的反应。然而,HIFs 在支链氨基酸 (BCAA) 代谢中的作用仍然未知。在人类胶质母细胞瘤 (GBM) 中,我们发现缺氧上调 BCAA 转运蛋白 LAT1 和 BCAA 代谢酶 BCAT1 的 mRNA 和蛋白水平,而不是它们的副 LAT2-4 和 BCAT2 细胞系以及原代 GBM 细胞。缺氧诱导的 LAT1 蛋白上调在 GBM 细胞中是由 HIF-1 和 HIF-2 共同介导的。虽然 hif-1 α 和 hif-2 α 都直接与人 BCAT1 基因第一内含子处的缺氧反应元件结合,但 hif-1 α 专门负责缺氧诱导的 GBM 细胞 BCAT1 表达。敲除 hif-1 α 和 hif-2 α 可显著减少缺氧条件下 GBM 细胞中 BCAAs 的谷氨酸标记,为 HIF 介导的 BCAA 代谢重编程提供了功能证据。遗传或药理学抑制 BCAT1 在缺氧条件下抑制 GBM 细胞生长。总之,这些发现揭示了一个以前未被认识的 HIF 依赖性代谢途径,在低氧应激条件下增加 GBM 细胞生长。

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DOI:10.1002/jmri.26786
作者列表:["Bhattacharjee R","Gupta RK","Patir R","Vaishya S","Ahlawat S","Singh A"]

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