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Updated: Jan 17, 2026

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

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PRC2/FOXO1-Mediated Repression Determines Interchangeability of ETS Oncogenes in Prostate Cancer and Ewing Sarcoma

Nicholas F Downing1, Kaitlyn M Mills1, Peter C Hollenhorst1

  • 1Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.

Molecular Cancer Research : MCR
|September 19, 2025
PubMed

Insights

Prostate cancer and Ewing sarcoma share common ETS transcription factor mechanisms. Targeting these shared pathways offers potential for novel therapeutic strategies against both cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Chromosomal rearrangements involving ETS transcription factors are prevalent in prostate cancer (60-70%) and Ewing sarcoma (>95%).
  • These rearrangements lead to aberrant ETS protein expression or fusion proteins, such as EWSR1::FLI1 in Ewing sarcoma.
  • ETS factors like ETV1, ETV4, ETV5, and ERG in prostate cancer can interact with EWSR1, suggesting shared molecular mechanisms.

Purpose of the Study:

  • To investigate the functional similarities between ETS transcription factors in prostate cancer and Ewing sarcoma.
  • To elucidate the role of EWSR1 and Polycomb Repressive Complex 2 (PRC2) in the oncogenic activity of these ETS factors.
  • To identify potential therapeutic targets based on common mechanisms.

Main Methods:

  • Utilized Ewing sarcoma cell lines to assess the functional impact of ETV1, ETV4, ETV5, and ERG.
  • Performed knockdown experiments for EWSR1::FLI1 and rescue experiments with ERG mutants.
  • Investigated the interaction between ERG, PRC2, and FOXO1 using biochemical assays.

Main Results:

  • ETV1, ETV4, and ETV5 phenocopied EWSR1::FLI1 in Ewing sarcoma models.
  • ERG-mediated rescue of EWSR1::FLI1 knockdown was dependent on disrupting PRC2 interaction.
  • Identified an endogenous PRC2/FOXO1 complex where FOXO1 mediates ERG/PRC2 binding.
  • AKT-mediated degradation of FOXO1 was linked to ERG synergy with PTEN deletion in prostate cancer.

Conclusions:

  • ETS transcription factors driving prostate cancer and Ewing sarcoma employ similar oncogenic mechanisms.
  • The interaction between ERG and PRC2, modulated by FOXO1, is a key pathway.
  • These shared mechanisms present opportunities for developing unified therapeutic strategies for both cancers.

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