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 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.
Authors
- Emeline Mariavelle
- Loïc Ongena (ORCID: https://orcid.org/0000-0002-7768-1428)
- Florencia Cidre‐Aranaz (ORCID: https://orcid.org/0000-0002-0246-7179)
- Thomas G. P. Grünewald (ORCID: https://orcid.org/0000-0003-0920-7377)
- Roland Imle (ORCID: https://orcid.org/0000-0001-9564-6952)
- Bartimée Galvan (ORCID: https://orcid.org/0000-0001-8629-4860)
- Lianghao Mao
- Grégory Fettweis (ORCID: https://orcid.org/0000-0002-6623-2264)
- Florian H. Geyer
- Véronique Kruys (ORCID: https://orcid.org/0000-0002-3144-5403)
- Ashok Kumar Jayavelu (ORCID: https://orcid.org/0000-0002-3292-1117)
- Jonathan Bruyr
- Tina O’Grady (ORCID: https://orcid.org/0000-0002-1283-0293)
- Kevin A. W. Lee
- Arnaud Lavergne (ORCID: https://orcid.org/0000-0003-4817-3202)
- Ana Banito (ORCID: https://orcid.org/0000-0003-2188-0003)
- Enrico Lucarelli (ORCID: https://orcid.org/0000-0002-6681-6374)
- Éric Hervouet (ORCID: https://orcid.org/0000-0002-4841-7812)
- Jules Durand
- Samuel Dequiedt (ORCID: https://orcid.org/0000-0003-1234-7477)
- Cyril Gueydan (ORCID: https://orcid.org/0000-0003-3097-7667)
- Jean‐Claude Twizere (ORCID: https://orcid.org/0000-0002-8683-705X)
- Zahra Al Oula Hassoun (ORCID: https://orcid.org/0000-0001-6125-2867)
- Laurence Dubois
- Margaux Claes
Institutions
- Tulane University (US)
- Scripps Research Institute (US)
- National Institutes of Health (US)
- Inserm (FR)
- University of Liège (BE)
- MRC Laboratory of Molecular Biology (GB)
- German Cancer Research Center (DE)
- Hong Kong University of Science and Technology (HK)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- University Children's Hospital Zurich (CH)
- National Cancer Institute (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Hong Kong (HK)
- Université de Franche-Comté (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41467-025-61725-x
- Citations
- 2
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Bundesministerium für Bildung und Forschung
- Fonds De La Recherche Scientifique - FNRS
- Université de Liège
- Deutsche Krebshilfe
- Fonds Léon Fredericq
- Universitatea din București