GPT2 Is Induced by Hypoxia-Inducible Factor (HIF)-2 and Promotes Glioblastoma Growth

Bo Zhang, Yan Chen, Lei Bao, Weibo Luo

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene in human glioblastoma (GBM). Hypoxia upregulated GPT2 mRNA and protein levels in GBM cells, which required HIF-2 but not HIF-1. HIF-2 directly bound to the hypoxia response element of the human GPT2 gene, leading to its transcription in hypoxic GBM cells. GPT2 located at the nucleus and mitochondria and reduced α-ketoglutarate levels in GBM cells. Genetic or pharmacological inhibition of GPT2 decreased GBM cell growth and migration under normoxia and hypoxia. Knockout of GPT2 inhibited GBM tumor growth in mice. Collectively, these findings uncover a hypoxia-inducible aminotransferase GPT2 required for GBM progression.

Original languageEnglish (US)
Article number2597
JournalCells
Volume11
Issue number16
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • glioblastoma
  • GPT2
  • hypoxia
  • hypoxia-inducible factor
  • tumorigenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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