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

Research output: Contribution to journalArticle

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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
StatePublished - Jun 30 2016

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Triple Negative Breast Neoplasms
Cysteine
Glutamic Acid
Breast Neoplasms
Prolyl Hydroxylases
Antiporters
Cystine
Assays
Transcription Factors
Oxygen
Degradation
Growth
Neoplasms

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

Paracrine Induction of HIF by Glutamate in Breast Cancer : EglN1 Senses Cysteine. / Briggs, Kimberly J J.; Koivunen, Peppi; Cao, Shugeng; Backus, Keriann M M.; Olenchock, Benjamin A A.; Patel, Hetalben; Zhang, Qing; Signoretti, Sabina; Gerfen, Gary J J.; Richardson, Andrea L L.; Witkiewicz, Agnieszka K K.; Cravatt, Benjamin F F.; Clardy, Jon; Kaelin, William G G.

In: Cell, Vol. 166, No. 1, 30.06.2016, p. 126-139.

Research output: Contribution to journalArticle

Briggs, KJJ, Koivunen, P, Cao, S, Backus, KMM, Olenchock, BAA, Patel, H, Zhang, Q, Signoretti, S, Gerfen, GJJ, Richardson, ALL, Witkiewicz, AKK, Cravatt, BFF, Clardy, J & Kaelin, WGG 2016, 'Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine', Cell, vol. 166, no. 1, pp. 126-139. https://doi.org/10.1016/j.cell.2016.05.042
Briggs KJJ, Koivunen P, Cao S, Backus KMM, Olenchock BAA, Patel H et al. Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Cell. 2016 Jun 30;166(1):126-139. https://doi.org/10.1016/j.cell.2016.05.042
Briggs, Kimberly J J. ; Koivunen, Peppi ; Cao, Shugeng ; Backus, Keriann M M. ; Olenchock, Benjamin A A. ; Patel, Hetalben ; Zhang, Qing ; Signoretti, Sabina ; Gerfen, Gary J J. ; Richardson, Andrea L L. ; Witkiewicz, Agnieszka K K. ; Cravatt, Benjamin F F. ; Clardy, Jon ; Kaelin, William G G. / Paracrine Induction of HIF by Glutamate in Breast Cancer : EglN1 Senses Cysteine. In: Cell. 2016 ; Vol. 166, No. 1. pp. 126-139.
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AU - Olenchock, Benjamin A A.

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AU - Signoretti, Sabina

AU - Gerfen, Gary J J.

AU - Richardson, Andrea L L.

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AU - Kaelin, William G G.

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