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Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.

par Galvan, Bartimee;Ongena, Loïc;Bruyr, Jonathan;Fettweis, Gregory;Lucarelli, Eva;Lavergne, Arnaud;Mariavelle, Emeline;O'Grady, Tina M;Hassoun, Zahrat El Oula;Claes, Margaux;Dubois, Laurence;Lee, Kevin A W;Kruys, Véronique ;Gueydan, Cyril ;Durand, Jules;Hervouet, Eric;Geyer, Florian FH;Banito, Ana;Imle, Roland;Mao, Lianghao;Jayavelu, Ashok AK;Grünewald, Thomas TGP;Cidre-Aranaz, Florencia;Twizere, Jean-Claude;Dequiedt, Franck
Référence Nature communications, 16, 1, page (6537)
Publication Publié, 2025-07-01

Article révisé par les pairs

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Résumé :

Many cancers are defined by gene fusions that frequently encode oncogenic transcription factors (TFs), such as EWSR1::FLI1 in Ewing sarcoma (EwS). Here, we report that independently to its canonical roles in transcription, EWSR1::FLI1 also functions as an mRNA decay factor, reshaping mRNA stability in EwS. This function participates in EWSR1::FLI1 tumorigenicity and involves interactions of EWSR1::FLI1 with the CCR4-NOT deadenylation complex via its EWSR1-derived low-complexity domain and with the RNA-binding protein HuR/ELAVL1 via its FLI1-derived region. Strikingly, we find that EWSR1::FLI1-mediated mRNA decay antagonizes the normal mRNA protective function of HuR and renders EwS cells highly sensitive to HuR inhibition. Our findings uncover a post-transcriptional function of EWSR1::FLI1 and suggest that targeting mRNA stability mechanisms may offer therapeutic opportunities for EwS.