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

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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.

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Acknowledgements

We would thank to Jennifer E. Wang for proofreading. This work was supported by grants from the NIH (R00CA168746, R01CA222393), Welch Foundation (I-1903), and the CPRIT (RR140036, RP190358) to W.L., and the NIH (R00NS078049, R01AG066166, and R35GM124693), CPRIT (RP170671), and Welch Foundation (I-1939) to Y.W. W.L. is a CPRIT Scholar in Cancer Research.

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  1. Bo Zhang and Yan Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75390-9072, USA

    Bo Zhang, Yan Chen, Mi Zhou, Lei Bao, Kimmo J. Hatanpaa, Yingfei Wang & Weibo Luo

  2. Children’s Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Xiaolei Shi & Ralph J. DeBerardinis

  3. Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Toral Patel

  4. Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Toral Patel & Yingfei Wang

  5. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Weibo Luo

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Contributions

WL, YW conceived the study, analyzed the data, and wrote the paper; BZ, YC, XS, MZ, BL performed experiments and analyzed the data; KH, TP provided fresh human glioblastoma tissues; RD analyzed the data. All authors read and approved the manuscript.

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Correspondence to Yingfei Wang or Weibo Luo.

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R.J.D. is an advisor for Agios Pharmaceuticals. Other authors declare that they have no conflict of interest.

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Zhang, B., Chen, Y., Shi, X. et al. Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma. Cell. Mol. Life Sci. 78, 195–206 (2021). https://doi.org/10.1007/s00018-020-03483-1

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