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Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing

Saravana P Selvanathan1, Garrett T Graham1, Hayriye V Erkizan1

  • 1Department of Oncology and Pediatrics, Georgetown University, Washington, DC 20057;

Proceedings of the National Academy of Sciences of the United States of America
|March 5, 2015
PubMed

Insights

Ewing sarcoma oncoprotein EWS-FLI1 drives cancer by altering messenger RNA (mRNA) splicing. Inhibiting EWS-FLI1 with YK-4-279 normalizes splicing patterns, offering a potential therapeutic strategy for Ewing sarcoma.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • Messenger RNA (mRNA) splicing is crucial for gene expression, with splice site selection modulated by various proteins.
  • Ewing sarcoma (ES) is driven by the EWS-FLI1 oncoprotein, which interacts with spliceosomal complexes.
  • Dysregulation of posttranscriptional gene regulation, including alternative splicing, is implicated in oncogenesis.

Purpose of the Study:

  • To investigate the impact of the EWS-FLI1 oncoprotein on mRNA splicing and posttranscriptional gene regulation in Ewing sarcoma.
  • To identify specific genes and splicing factors modulated by EWS-FLI1.
  • To evaluate the therapeutic potential of targeting EWS-FLI1-mediated splicing alterations.

Main Methods:

  • Exon array and RNA-sequencing (RNA-seq) were employed to analyze gene expression and splicing patterns.
  • CLIP-seq experiments were conducted to identify RNA-binding motifs of EWS-FLI1.
  • Protein-protein interaction studies were performed to assess EWS-FLI1 binding to splicing factors.
  • The effect of the EWS-FLI1 inhibitor YK-4-279 on splicing was evaluated.
  • Analysis of patient samples was performed using exon arrays.

Main Results:

  • EWS-FLI1 significantly alters the splicing of genes involved in oncogenesis, such as CLK1, CASP3, PPFIBP1, and TERT.
  • EWS-FLI1 binds to splicing factors like DDX5, hnRNP K, and PRPF6, directly influencing splicing.
  • Reduction of EWS-FLI1 leads to altered TERT splicing, impacting telomerase activity.
  • The inhibitor YK-4-279 mimics the splicing alterations observed upon EWS-FLI1 reduction.
  • Splicing patterns in ES patient samples resemble those in cell line models expressing EWS-FLI1.

Conclusions:

  • Systemic alternative splicing is an oncogenic process driven by EWS-FLI1 in Ewing sarcoma.
  • EWS-FLI1's modulation of mRNA splicing contributes to oncogenesis.
  • Targeting EWS-FLI1 interactions with splicing machinery, potentially via inhibitors like YK-4-279, represents a viable therapeutic strategy.
Keywords:
CLK1EWS-FLI1Ewing sarcomaTERTalternative splicing

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