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

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 and Franck Dequiedt ()
Additional contact information
Bartimée Galvan: University of Liège (ULiège)
Loïc Ongena: University of Liège (ULiège)
Jonathan Bruyr: University of Liège (ULiège)
Gregory Fettweis: University of Liège (ULiège)
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)
Zahrat El Oula Hassoun: University of Liège (ULiège)
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 »
Eric Hervouet: « Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique »
Florian H. Geyer: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Ana Banito: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Roland Imle: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Lianghao Mao: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Ashok K. Jayavelu: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Thomas G. P. Grünewald: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Florencia Cidre-Aranaz: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Jean-Claude Twizere: University of Liège (ULiège)
Franck Dequiedt: University of Liège (ULiège)

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61725-x

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