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

Bartimée Galvan1,2, Loïc Ongena1, Jonathan Bruyr1

  • 1Laboratory of Gene Expression and Cancer, GIGA Institute, University of Liège (ULiège), Liège, Belgium.

Nature Communications
|July 15, 2025
PubMed

Insights

EWSR1::FLI1, a transcription factor in Ewing sarcoma, also promotes cancer by accelerating mRNA decay. This newly found function makes cancer cells vulnerable to therapies targeting HuR.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Gene Regulation

Background:

  • Gene fusions, such as EWSR1::FLI1, are hallmarks of many cancers, including Ewing sarcoma (EwS).
  • EWSR1::FLI1 is known to function as an oncogenic transcription factor (TF).
  • The precise mechanisms by which EWSR1::FLI1 drives tumorigenesis are still being uncovered.

Purpose of the Study:

  • To investigate non-canonical functions of EWSR1::FLI1 beyond its role as a transcription factor.
  • To elucidate the role of EWSR1::FLI1 in regulating mRNA stability in Ewing sarcoma.
  • To identify potential therapeutic strategies targeting EWSR1::FLI1-mediated pathways.

Main Methods:

  • Investigated EWSR1::FLI1's function as an mRNA decay factor in EwS cells.
  • Analyzed interactions of EWSR1::FLI1 with the CCR4-NOT deadenylation complex and HuR/ELAVL1.
  • Assessed the impact of EWSR1::FLI1-mediated mRNA decay on cellular sensitivity to HuR inhibition.

Main Results:

  • EWSR1::FLI1 functions as an mRNA decay factor, independent of its transcriptional activity.
  • EWSR1::FLI1 interacts with the CCR4-NOT complex and the RNA-binding protein HuR.
  • EWSR1::FLI1-induced mRNA decay antagonizes HuR's protective function, sensitizing EwS cells to HuR inhibition.

Conclusions:

  • EWSR1::FLI1 possesses a novel post-transcriptional function in regulating mRNA stability.
  • This function contributes to EWSR1::FLI1-driven tumorigenesis in Ewing sarcoma.
  • Targeting mRNA stability pathways, particularly HuR, presents a potential therapeutic avenue for EwS.

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