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FOXO1 is a direct target of EWS-Fli1 oncogenic fusion protein in Ewing's sarcoma cells

Liu Yang1, Hsien-Ming Hu, Anna Zielinska-Kwiatkowska

  • 1Department of Orthopedics, University of Washington, Seattle, WA 98195, United States. lyang@u.washington.edu

Biochemical and Biophysical Research Communications
|October 12, 2010
PubMed

Insights

Ewing's sarcoma cells have an inverse relationship between EWS-Fli1 oncogenic protein and FOXO1 tumor suppressor expression. Suppressing EWS-Fli1 increases FOXO1, suggesting its role in Ewing's family tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ewing's family of tumors (EFTs) are aggressive bone and soft tissue cancers.
  • A hallmark of EFTs is the t(11;22) chromosomal translocation, creating the oncogenic EWS-Fli1 fusion protein.
  • The precise mechanisms by which EWS-Fli1 drives tumorigenesis are not fully elucidated.

Purpose of the Study:

  • To investigate the impact of EWS-Fli1 on gene expression in EFTs.
  • To identify novel targets of EWS-Fli1, focusing on the tumor suppressor FOXO1.
  • To characterize the regulatory relationship between EWS-Fli1 and FOXO1 in EFTs.

Main Methods:

  • DNA microarray analysis was performed following siRNA-mediated knockdown of EWS-Fli1.
  • A doxycycline-inducible siRNA system was established for stable and reversible EWS-Fli1 knockdown in EFT cells.
  • FOXO1 expression, promoter activity, and EWS-Fli1 binding to the FOXO1 promoter were assessed.

Main Results:

  • EWS-Fli1 knockdown led to increased expression of known repressed genes like DKK1 and p57.
  • FOXO1 expression and promoter activity were inversely correlated with EWS-Fli1 protein levels.
  • EWS-Fli1 binding to the FOXO1 promoter decreased upon EWS-Fli1 knockdown.

Conclusions:

  • EWS-Fli1 directly suppresses FOXO1 expression in Ewing's sarcoma cells.
  • The EWS-Fli1-mediated repression of FOXO1 may contribute to the cellular transformation observed in EFTs.
  • Targeting the EWS-Fli1/FOXO1 axis presents a potential therapeutic strategy for Ewing's family tumors.

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