%0 Journal Article
%A Galvan, Bartimée
%A Ongena, Loïc
%A Bruyr, Jonathan
%A Fettweis, Gregory
%A Lucarelli, Eva
%A Lavergne, Arnaud
%A Mariavelle, Emeline
%A O'Grady, Tina M
%A Hassoun, Zahrat El Oula
%A Claes, Margaux
%A Dubois, Laurence
%A Lee, Kevin A W
%A Kruys, Véronique
%A Gueydan, Cyril
%A Durand, Jules
%A Hervouet, Eric
%A Geyer, Florian
%A Banito, Ana
%A Imle, Roland
%A Mao, Lianghao
%A Jayavelu, Ashok K
%A Grünewald, Thomas
%A Cidre-Aranaz, Florencia
%A Twizere, Jean-Claude
%A Dequiedt, Franck
%T Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-01397
%P 6537
%D 2025
%X 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.
%K Sarcoma, Ewing: genetics
%K Sarcoma, Ewing: metabolism
%K Sarcoma, Ewing: pathology
%K Humans
%K Proto-Oncogene Protein c-fli-1: metabolism
%K Proto-Oncogene Protein c-fli-1: genetics
%K RNA Stability: genetics
%K RNA-Binding Protein EWS: metabolism
%K RNA-Binding Protein EWS: genetics
%K Cell Line, Tumor
%K Animals
%K Oncogene Proteins, Fusion: metabolism
%K Oncogene Proteins, Fusion: genetics
%K Mice
%K RNA, Messenger: metabolism
%K RNA, Messenger: genetics
%K RNA-Binding Proteins: metabolism
%K RNA-Binding Proteins: genetics
%K Gene Expression Regulation, Neoplastic
%K Bone Neoplasms: genetics
%K Bone Neoplasms: metabolism
%K Proto-Oncogene Protein c-fli-1 (NLM Chemicals)
%K EWSR1 protein, human (NLM Chemicals)
%K RNA-Binding Protein EWS (NLM Chemicals)
%K FLI1 protein, human (NLM Chemicals)
%K Oncogene Proteins, Fusion (NLM Chemicals)
%K RNA, Messenger (NLM Chemicals)
%K RNA-Binding Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40664627
%2 pmc:PMC12263829
%R 10.1038/s41467-025-61725-x
%U https://inrepo02.dkfz.de/record/302857