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EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway
Author(s) -
Mutz Cornelia N.,
Schwentner Raphaela,
Kauer Maximilian O.,
Katschnig Anna M.,
Kromp Florian,
Aryee Dave N. T.,
Erhardt Sophie,
Goiny Michel,
Alonso Javier,
Fuchs Dietmar,
Kovar Heinrich
Publication year - 2016
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12243
Subject(s) - aryl hydrocarbon receptor , kynurenine , chemistry , gene knockdown , kynurenic acid , aryl hydrocarbon receptor nuclear translocator , tryptophan , kynurenine pathway , receptor , metabolite , signal transduction , microbiology and biotechnology , cancer research , gene , biochemistry , biology , transcription factor , amino acid
Ewing sarcoma ( ES ) is an aggressive pediatric tumor driven by the fusion protein EWS ‐ FLI 1. We report that EWS ‐ FLI 1 suppresses TDO 2‐mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS ‐ FLI 1‐dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS ‐ FLI 1, 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 ‐ FLI 1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS ‐ FLI 1 suppresses autocrine AHR signaling by inhibiting TDO 2‐catalyzed TRP breakdown.
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