EWS-FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway.
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.
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Cornelia N
CN
Mutz
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Raphaela
R
Schwentner
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Maximilian O
MO
Kauer
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Anna M
AM
Katschnig
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Florian
F
Kromp
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University Vienna, Austria.
Dave N T
DN
Aryee
Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden.
Sophie
S
Erhardt
Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden.
Michel
M
Goiny
Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, ISCIII, Ctra, Madrid, Spain.
Javier
J
Alonso
Division of Biological Chemistry, Biocenter Innsbruck Medical University, Center for Chemistry and Biomedicine, Austria.
Dietmar
D
Fuchs
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University Vienna, Austria.
Heinrich
H
Kovar
D019898:Autocrine Communication; D002460:Cell Line; D006801:Humans; D007737:Kynurenine / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*
C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D018336:Receptors, Aryl Hydrocarbon; D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase
EWS-FLI1; aryl hydrocarbon receptor; tryptophan