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Updated: Oct 23, 2025

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Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1

Taylor R Nicholas1, Stephanie A Metcalf2, Benjamin M Greulich2

  • 1Department of Biology, Indiana University, Bloomington, IN 47405, USA.

NAR Cancer
|August 19, 2021
PubMed

Insights

Androgen signaling upregulates a specific EWSR1 gene isoform in prostate cancer, promoting cell growth and migration. This process involves R-loops and may lead to gene rearrangements, impacting cancer development.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • The EWSR1 gene is crucial in prostate cancer and Ewing sarcoma.
  • Understanding EWSR1 gene regulation is vital for cancer research.
  • EWSR1 protein's role in cell migration and growth is established.

Purpose of the Study:

  • To investigate the regulation of the EWSR1 gene in prostate cancer.
  • To identify mechanisms by which androgen signaling affects EWSR1 expression.
  • To explore the link between EWSR1 regulation, R-loops, and gene rearrangements.

Main Methods:

  • Analysis of EWSR1 gene expression in prostate cancer cells.
  • Investigating the role of intronic polyadenylation sites.
  • Studying Androgen Receptor (AR) binding and its effect on EWSR1.
  • Assessing R-loop formation and DNA breakage using molecular techniques.
  • Utilizing RNase H to probe R-loop dependent mechanisms.

Main Results:

  • Androgen signaling upregulates a 5' EWSR1 isoform via an intronic polyadenylation site.
  • This EWSR1 isoform enhances cell migration and clonogenic growth.
  • Deletion of an AR binding site abrogates androgen-dependent EWSR1 upregulation.
  • Androgen signaling promotes R-loop and breakpoint formation near the 5' EWSR1 site.
  • RNase H reduces EWSR1 isoform expression and DNA breakage, indicating an R-loop dependent mechanism.

Conclusions:

  • Androgen signaling drives expression of a pro-migratory EWSR1 isoform in prostate cancer.
  • R-loop formation within the EWSR1 gene is implicated in its altered regulation and potential rearrangements.
  • These findings reveal a novel regulatory pathway for EWSR1 influenced by androgen signaling, with implications for both prostate cancer and Ewing sarcoma.

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