title: Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Briggs
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shugeng
authors.initials: S
authors.lastname: Cao
authors.affiliation: The Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Keriann M
authors.initials: KM
authors.lastname: Backus
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Olenchock
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Hetalben
authors.initials: H
authors.lastname: Patel
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Gerfen
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: The Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: 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.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D019899:Paracrine Communication; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D027182:Amino Acid Transport System y+; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D003545:Cysteine