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

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...

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Main Authors: Galvan, Bartimée (Author) , Ongena, Loïc (Author) , Bruyr, Jonathan (Author) , Fettweis, Gregory (Author) , Lucarelli, Eva (Author) , Lavergne, Arnaud (Author) , Mariavelle, Emeline (Author) , O’Grady, Tina M. (Author) , Hassoun, Zahrat El Oula (Author) , Claes, Margaux (Author) , Dubois, Laurence (Author) , Lee, Kevin A. W. (Author) , Kruys, Véronique (Author) , Gueydan, Cyril (Author) , Durand, Jules (Author) , Hervouet, Eric (Author) , Geyer, Florian H. (Author) , Banito, Ana (Author) , Imle, Roland (Author) , Mao, Lianghao (Author) , Jayavelu, Ashok Kumar (Author) , Grünewald, Thomas G. P. (Author) , Cidre-Aranaz, Florencia (Author) , Twizere, Jean-Claude (Author) , Dequiedt, Franck (Author)
Format: Article (Journal)
Language:English
Published: 16 July 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-24
ISSN:2041-1723
DOI:10.1038/s41467-025-61725-x
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-61725-x
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-61725-x
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Author Notes:Bartimée Galvan, Loïc Ongena, Jonathan Bruyr, Gregory Fettweis, Eva Lucarelli, Arnaud Lavergne, Emeline Mariavelle, Tina M. O’Grady, Zahrat El Oula Hassoun, Margaux Claes, Laurence Dubois, Kevin A.W. Lee, Véronique Kruys, Cyril Gueydan, Jules Durand, Eric Hervouet, Florian H. Geyer, Ana Banito, Roland Imle, Lianghao Mao, Ashok K. Jayavelu, Thomas G.P. Grünewald, Florencia Cidre-Aranaz, Jean-Claude Twizere & Franck Dequiedt
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Summary: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.
Item Description:Gesehen am 28.11.2025
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-61725-x

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