Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine

Kimberly J J. Briggs, Peppi Koivunen, Shugeng Cao, Keriann M M. Backus, Benjamin A A. Olenchock, Hetalben Patel, Qing Zhang, Sabina Signoretti, Gary J J. Gerfen, Andrea L L. Richardson, Agnieszka K K. Witkiewicz, Benjamin F F. Cravatt, Jon Clardy, William G G. Kaelin

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Abstract

The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIFα prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1α accumulation. Therefore, EglN1 senses both oxygen and cysteine.

Original languageEnglish (US)
Pages (from-to)126-139
Number of pages14
JournalCell
Volume166
Issue number1
DOIs
Publication statusPublished - Jun 30 2016

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Briggs, KJ. J., Koivunen, P., Cao, S., Backus, KM. M., Olenchock, BA. A., Patel, H., ... Kaelin, WG. G. (2016). Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Cell, 166(1), 126-139. https://doi.org/10.1016/j.cell.2016.05.042