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.

中文翻译：

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胶质母细胞瘤中缺氧诱导因子对支链氨基酸代谢的调节。


缺氧诱导因子（HIF）介导响应缺氧的代谢重编程。然而，HIF 在支链氨基酸 (BCAA) 代谢中的作用仍不清楚。在这里，我们发现，在人胶质母细胞瘤 (GBM) 细胞系以及原代 GBM 细胞中，缺氧会上调 BCAA 转运蛋白 LAT1 和 BCAA 代谢酶 BCAT1 的 mRNA 和蛋白质水平，但不会上调其旁系同源物 LAT2-4 和 BCAT2。 GBM 细胞中缺氧诱导的 LAT1 蛋白上调由 HIF-1 和 HIF-2 介导。尽管 HIF-1α 和 HIF-2α 都直接与人 BCAT1 基因第一个内含子处的缺氧反应元件结合，但 HIF-1α 专门负责 GBM 细胞中缺氧诱导的 BCAT1 表达。敲除 HIF-1α 和 HIF-2α 显着降低缺氧条件下 GBM 细胞中 BCAA 的谷氨酸标记，这为 HIF 介导的 BCAA 代谢重编程提供了功能证据。 BCAT1 的遗传或药理学抑制可抑制缺氧下 GBM 细胞的生长。总之，这些发现揭示了一种以前未被认识的 HIF 依赖性代谢途径，该途径在缺氧应激条件下会增加 GBM 细胞的生长。