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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Breast Neoplasms / metabolism*
  • Cysteine / metabolism*
  • Glutamic Acid / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • MCF-7 Cells
  • Mice
  • Paracrine Communication*
  • Triple Negative Breast Neoplasms / metabolism*

Substances

  • Amino Acid Transport System y+
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • SLC7A11 protein, human
  • Glutamic Acid
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Cysteine