Open AccessParacrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine
Author(s) -
Kimberly J. Briggs,
Peppi Koivunen,
Shugeng Cao,
Keriann M. Backus,
Benjamin A. Olenchock,
Hetalben Patel,
Qing Zhang,
Sabina Signoretti,
Gary J. Gerfen,
Andrea L. Richardson,
Agnieszka K. Witkiewicz,
Benjamin F. Cravatt,
Jon Clardy,
William G. Kaelin
Publication year - 2016
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2016.05.042
Subject(s) - biology , paracrine signalling , cysteine , glutamate receptor , microbiology and biotechnology , cancer cell , hypoxia inducible factors , transcription factor , biochemistry , cancer research , cancer , gene , genetics , receptor , enzyme
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.
Accelerating Research
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom
Address
John Eccles HouseRobert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom