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. ; The authors thank Dr. Peter Münzel for providing the pT81/3xDRE plasmid. We also thank Dr. Andreas Heitger posthumously for critical discussion and scientific advice. Austrian Science Fund (FWF), ERA‐NET TransCan project PROVABES, project number I 1225‐B19; European Union's FP7 project ASSET (grant agreement No. 259348). J.A. is supported by Asociación Pablo Ugarte and Miguelañez S.A, ASION‐La Hucha de Tomás, Fundación La Sonrisa de Alex and Instituto de Salud Carlos III (PI12/00816 and Spanish Cancer Network RTICC RD12/0036/0027); the Swedish Medical Research Council (2009‐7053; 2013‐2838). ; Sí