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Cell. 2016 Jun 30;166(1):126-39. doi: 10.1016/j.cell.2016.05.042.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA 02215, USA.
2
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
4
The Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
5
Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
7
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
8
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.

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.

PMID:
27368101
PMCID:
PMC4930557
DOI:
10.1016/j.cell.2016.05.042
[Indexed for MEDLINE]
Free PMC Article

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