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Updated: Jul 9, 2025

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
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Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer

Laura Helminen1, Jasmin Huttunen1, Melina Tulonen1

  • 1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.

Nucleic Acids Research
|November 28, 2023
PubMed

Insights

Glucocorticoid receptor (GR) can replace androgen receptor (AR) in prostate cancer, driving resistance to antiandrogen therapies. We found FOXA1 represses GR, and inhibiting p300 blocks GR activity, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genomics

Background:

  • Prostate cancer treatment often involves androgen receptor (AR) signaling inhibition.
  • Cancer cells can develop resistance to antiandrogen therapies.
  • Glucocorticoid receptor (GR) can mediate resistance by replacing AR function, but mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanisms of GR-mediated antiandrogen resistance in prostate cancer.
  • To identify key regulators of GR action in this context.

Main Methods:

  • Genome-wide techniques were employed to study GR action in prostate cancer cells.
  • Analysis of chromatin accessibility and transcription factor occupancy (FOXA1).
  • Gene silencing (FOXA1) and small-molecule inhibition (p300 coactivator).

Main Results:

  • GR replaces AR at pre-accessible chromatin sites marked by FOXA1 in resistant cells.
  • FOXA1 silencing enhanced GR chromatin binding and activity.
  • FOXA1 represses NR3C1 (GR gene) expression via TLE3 corepressor.
  • Inhibiting p300's enzymatic activity blocked GR-mediated gene regulation and proliferation.

Conclusions:

  • Chromatin pre-accessibility and FOXA1-mediated repression are critical regulators of GR action in prostate cancer.
  • These findings reveal novel strategies to overcome steroid receptor-mediated antiandrogen resistance.

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