TY - JOUR
T1 - Paracrine Induction of HIF by Glutamate in Breast Cancer
T2 - EglN1 Senses Cysteine
AU - Briggs, Kimberly J J.
AU - Koivunen, Peppi
AU - Cao, Shugeng
AU - Backus, Keriann M M.
AU - Olenchock, Benjamin A A.
AU - Patel, Hetalben
AU - Zhang, Qing
AU - Signoretti, Sabina
AU - Gerfen, Gary J J.
AU - Richardson, Andrea L L.
AU - Witkiewicz, Agnieszka K K.
AU - Cravatt, Benjamin F F.
AU - Clardy, Jon
AU - Kaelin, William G G.
N1 - Funding Information:
We thank members of the Kaelin Laboratory for useful discussions, Gang Lu for multiple reagents and cloning advice, Jason Marineau for fractionation advice and reagents, Julie Losman for her FACS expertise, Amanda Silva for performing gavage, and Humayun Sharif and Michael Eck for generating Figure 6 I. This work was supported by grants to W.G.K. from the NIH and the Breast Cancer Research Foundation and T32 and F32 NIH training grants to K.J.B. W.G.K. is an HHMI Investigator.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/30
Y1 - 2016/6/30
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2016.05.042
DO - 10.1016/j.cell.2016.05.042
M3 - Article
C2 - 27368101
AN - SCOPUS:84976907997
SN - 0092-8674
VL - 166
SP - 126
EP - 139
JO - Cell
JF - Cell
IS - 1
ER -
