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The cell cycle regulator CCDC6 is a key target of RNA-binding protein EWS

Sujitha Duggimpudi1, Erik Larsson2, Schafiq Nabhani1

  • 1Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.

Plos One
|March 10, 2015
PubMed

Insights

Ewing sarcoma involves EWSR1 gene translocations. This study reveals wild-type EWSR1 regulates cell cycle protein CCDC6, impacting apoptosis, offering new therapeutic insights.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ewing sarcoma is primarily caused by EWSR1 gene translocations fusing it with ETS transcription factors.
  • Research has focused on the chimeric proteins, but the role of wild-type EWSR1 loss remains unclear.
  • Previous work identified messenger RNAs (mRNAs) bound by the EWS protein using Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP).

Purpose of the Study:

  • To investigate the physiological consequences of heterozygous EWSR1 loss in Ewing sarcoma.
  • To identify novel targets regulated by the wild-type EWS protein.
  • To elucidate the functional role of EWS in Ewing sarcoma pathogenesis.

Main Methods:

  • Utilized previously generated PAR-CLIP data to identify EWS-bound mRNAs.
  • Employed small interfering RNA (siRNA) to downregulate EWS expression.
  • Assessed apoptosis levels and performed rescue experiments by re-expressing CCDC6.

Main Results:

  • Identified CCDC6, a known cell cycle regulator, as a novel target directly regulated by EWS.
  • siRNA-mediated knockdown of EWS led to increased apoptosis in cancer cells.
  • The pro-apoptotic effect of EWS downregulation was dependent on CCDC6 levels and could be rescued by CCDC6 re-expression.

Conclusions:

  • Wild-type EWS plays a crucial role in Ewing sarcoma by regulating the cell cycle through CCDC6.
  • EWS exerts its function in a target-dependent manner, highlighting CCDC6 as a key mediator.
  • This study uncovers a novel mechanism of EWS function and suggests potential therapeutic strategies targeting the EWS-CCDC6 axis.

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