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

Bo Zhang, Yan Chen, Xiaolei Shi, Mi Zhou, Lei Bao, Kimmo J. Hatanpaa, Toral Patel, Ralph J. DeBerardinis, Yingfei Wang, Weibo Luo

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)195-206
Number of pages12
JournalCellular and Molecular Life Sciences
Volume78
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • Branched-chain amino acid
  • Gene regulation
  • Glioblastoma
  • Hypoxia
  • Hypoxia-inducible factor
  • Metabolism

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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