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

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.

• Authors: Bo Zhang, Yan Chen, Xiaolei Shi, Mi Zhou, Lei Bao, Kimmo J Hatanpaa, Toral Patel, Ralph J DeBerardinis, Yingfei Wang, Weibo Luo
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 78 Issue 1 Pg. 195-206 (Jan 2021) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 32088728 (Publication Type: Journal Article)

Chemical References

• Amino Acids, Branched-Chain
• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Large Neutral Amino Acid-Transporter 1
• SLC7A5 protein, human
• endothelial PAS domain-containing protein 1
• Glutamic Acid
• BCAT1 protein, human
• Transaminases

Topics

• Amino Acids, Branched-Chain (metabolism)
• Basic Helix-Loop-Helix Transcription Factors (deficiency, genetics, metabolism)
• Brain Neoplasms (metabolism, pathology)
• CRISPR-Cas Systems (genetics)
• Cell Hypoxia
• Cell Proliferation
• Cells, Cultured
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• Glioblastoma (metabolism, pathology)
• Glutamic Acid (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (deficiency, genetics, metabolism)
• Large Neutral Amino Acid-Transporter 1 (genetics, metabolism)
• Protein Binding
• Transaminases (antagonists & inhibitors, genetics, metabolism)