Open AccessRegulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma
Author(s) -
Bo Zhang,
Yan Chen,
Xiaolei Shi,
Mi Zhou,
Lei Bao,
Kimmo J. Hatanpaa,
Toral Patel,
Ralph J. DeBerardinis,
Yingfei Wang,
Weibo Luo
Publication year - 2020
Publication title -
cellular and molecular life sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.928
H-Index - 223
eISSN - 1420-9071
pISSN - 1420-682X
DOI - 10.1007/s00018-020-03483-1
Subject(s) - hypoxia (environmental) , downregulation and upregulation , hypoxia inducible factors , reprogramming , biology , metabolism , cell culture , cell growth , microbiology and biotechnology , branched chain amino acid , cell , cancer research , chemistry , amino acid , biochemistry , gene , leucine , genetics , organic chemistry , oxygen
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.