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

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

  • Nat Commun. 2025 Jul 16;16(1):6537. doi: 10.1038/s41467-025-61725-x.
Bartimée Galvan 1 2,  Loïc Ongena 1,  Jonathan Bruyr 1,  Gregory Fettweis 1 3,  Eva Lucarelli 1,  Arnaud Lavergne 4,  Emeline Mariavelle 1,  Tina M O'Grady 1 5,  Zahrat El Oula Hassoun 1 6,  Margaux Claes 1,  Laurence Dubois 1,  Kevin A W Lee 7,  Véronique Kruys 8,  Cyril Gueydan 8,  Jules Durand 9 10,  Eric Hervouet 9 10,  Florian H Geyer 11 12 13,  Ana Banito 11 14,  Roland Imle 11 14 15,  Lianghao Mao 11 12 16,  Ashok K Jayavelu 11 12 16,  Thomas G P Grünewald 11 12 13 17,  Florencia Cidre-Aranaz 11 12 13,  Jean-Claude Twizere 18,  Franck Dequiedt 19
Affiliations

Affiliations

  • 1 Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège (ULiège), Liège, Belgium.
  • 2 Division of Oncology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
  • 3 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, USA.
  • 4 Genomics Platform, GIGA Institute, University of Liège (ULiège), Liège, Belgium.
  • 5 Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, USA.
  • 6 Department of Integrative Structural and Computational Biology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, USA.
  • 7 Division of Life Science, The Hong Kong University of Sci. & Tech, Clear Water Bay, Kowloon, Hong Kong SAR, China.
  • 8 Laboratory of Molecular Biology of the Gene, Department of Molecular Biology, Free University of Brussels (ULB), 6041, Gosselies, Belgium.
  • 9 Université Franche-Comté, INSERM, EFS BFC, UMR1098, « Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique », F-25000, Besançon, France.
  • 10 EPIGENExp platform, Université Franche-Comté, F-25000, Besançon, France.
  • 11 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • 12 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • 13 Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 14 Soft-Tissue Sarcoma research group (B380), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15 Department of pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
  • 16 Research Group Proteomics and Cancer Cell Signaling, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • 17 Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 18 Laboratory of Viral Interactomes Networks, GIGA Institute, University of Liège (ULiège), 4000, Liège, Belgium.
  • 19 Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège (ULiège), Liège, Belgium. fdequiedt@uliege.be.
PMID: 40664627 DOI: 10.1038/s41467-025-61725-x
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124828
    98.66%, HuR-ARE Interaction Inhibitor
    HuR