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<p>Many cancers are defined by gene fusions that frequently encode&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月16日

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  • 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

摘要

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.