Fiche publication
Date publication
juillet 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERVOUET Eric
Tous les auteurs :
Galvan B, Ongena L, Bruyr J, Fettweis G, Lucarelli E, Lavergne A, Mariavelle E, O'Grady TM, Hassoun ZEO, Claes M, Dubois L, Lee KAW, Kruys V, Gueydan C, Durand J, Hervouet E, Geyer FH, Banito A, Imle R, Mao L, Jayavelu AK, Grünewald TGP, Cidre-Aranaz F, Twizere JC, Dequiedt F
Lien Pubmed
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.
Mots clés
Sarcoma, Ewing, genetics, Humans, Proto-Oncogene Protein c-fli-1, metabolism, RNA Stability, genetics, RNA-Binding Protein EWS, metabolism, Cell Line, Tumor, Animals, Oncogene Proteins, Fusion, metabolism, Mice, RNA, Messenger, metabolism, RNA-Binding Proteins, metabolism, Gene Expression Regulation, Neoplastic, Bone Neoplasms, genetics
Référence
Nat Commun. 2025 07 16;16(1):6537
