EWS-FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

FEBS Lett. 2016 Jul;590(14):2063-75. doi: 10.1002/1873-3468.12243. Epub 2016 Jun 21.

Abstract

Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS-FLI1. We report that EWS-FLI1 suppresses TDO2-mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS-FLI1-dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS-FLI1, resulting in kynurenine and kynurenic acid accumulation, both aryl hydrocarbon receptor (AHR) ligands. Activated AHR binds to the promoter region of target genes. We demonstrate that EWS-FLI1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS-FLI1 suppresses autocrine AHR signaling by inhibiting TDO2-catalyzed TRP breakdown.

Keywords: EWS-FLI1; aryl hydrocarbon receptor; tryptophan.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autocrine Communication*
  • Cell Line
  • Humans
  • Kynurenine / genetics
  • Kynurenine / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Proto-Oncogene Protein c-fli-1 / metabolism*
  • RNA-Binding Protein EWS / genetics
  • RNA-Binding Protein EWS / metabolism*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction*
  • Tryptophan / genetics
  • Tryptophan / metabolism*
  • Tryptophan Oxygenase / genetics
  • Tryptophan Oxygenase / metabolism*

Substances

  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • Receptors, Aryl Hydrocarbon
  • Kynurenine
  • Tryptophan
  • Tryptophan Oxygenase