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

Author

Listed:
  • Bartimée Galvan

    (University of Liège (ULiège)
    University Children’s Hospital Zurich)

  • Loïc Ongena

    (University of Liège (ULiège))

  • Jonathan Bruyr

    (University of Liège (ULiège))

  • Gregory Fettweis

    (University of Liège (ULiège)
    National Institutes of Health)

  • Eva Lucarelli

    (University of Liège (ULiège))

  • Arnaud Lavergne

    (University of Liège (ULiège))

  • Emeline Mariavelle

    (University of Liège (ULiège))

  • Tina M. O’Grady

    (University of Liège (ULiège)
    Tulane University School of Medicine)

  • Zahrat El Oula Hassoun

    (University of Liège (ULiège)
    The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

  • Margaux Claes

    (University of Liège (ULiège))

  • Laurence Dubois

    (University of Liège (ULiège))

  • Kevin A. W. Lee

    (Clear Water Bay)

  • Véronique Kruys

    (Free University of Brussels (ULB))

  • Cyril Gueydan

    (Free University of Brussels (ULB))

  • Jules Durand

    (« Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique »
    Université Franche-Comté)

  • Eric Hervouet

    (« Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique »
    Université Franche-Comté)

  • Florian H. Geyer

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    a partnership between DKFZ and Heidelberg University Hospital
    German Cancer Consortium (DKTK))

  • Ana Banito

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Research Center (DKFZ))

  • Roland Imle

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Lianghao Mao

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    a partnership between DKFZ and Heidelberg University Hospital
    Hopp Children’s Cancer Center Heidelberg (KiTZ))

  • Ashok K. Jayavelu

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    a partnership between DKFZ and Heidelberg University Hospital
    Hopp Children’s Cancer Center Heidelberg (KiTZ))

  • Thomas G. P. Grünewald

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    a partnership between DKFZ and Heidelberg University Hospital
    German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Florencia Cidre-Aranaz

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    a partnership between DKFZ and Heidelberg University Hospital
    German Cancer Consortium (DKTK))

  • Jean-Claude Twizere

    (University of Liège (ULiège))

  • Franck Dequiedt

    (University of Liège (ULiège))

Abstract

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.

Suggested Citation

  • 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 & , 2025. "Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61725-x
    DOI: 10.1038/s41467-025-61725-x
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    References listed on IDEAS

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