Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma
Year: 2025
Type: article
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. The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.
Source: Nature Communications
Authors: 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
Institutions: University of Liège, University Children's Hospital Zurich, National Institutes of Health, National Cancer Institute, Tulane University, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Hong Kong University of Science and Technology, Université Libre de Bruxelles, Inserm, Interactions Hôte-Greffon-Tumeur & Ingénierie Cellulaire et Génique, Université de Franche-Comté, German Cancer Research Center, Heidelberg University, University Hospital Heidelberg, National Center for Tumor Diseases, Hopp Children's Cancer Center Heidelberg, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W4412486992