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Updated: Oct 21, 2025

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
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An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

Alastair Davies1,2, Shaghayegh Nouruzi1,2, Dwaipayan Ganguli2

  • 1Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Nature Cell Biology
|September 7, 2021
PubMed

Insights

Prostate cancers adapt to therapies by changing cell type. Targeting the enhancer of zeste homologue 2 (EZH2) and androgen receptor (AR) can reverse this resistance, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Cancers adapt to targeted therapies by altering their cellular phenotype.
  • Prostate cancer can transition to a high-plasticity state to resist androgen receptor (AR) antagonism.

Purpose of the Study:

  • Investigate adaptive resistance mechanisms in prostate cancer.
  • Elucidate the role of the epigenetic regulator enhancer of zeste homologue 2 (EZH2) in AR-antagonist resistance.
  • Explore therapeutic strategies to reverse lineage infidelity.

Main Methods:

  • Analysis of AR activity and chromatin architecture changes.
  • Investigated the role of EZH2 in modulating stem cell and neuronal gene networks.
  • Studied EZH2 phosphorylation at T350 and non-canonical polycomb complex formation.

Main Results:

  • AR activity is maintained during lineage transition.
  • EZH2 co-occupies the reprogrammed AR cistrome, modulating stem cell and neuronal gene expression.
  • EZH2's function is linked to T350 phosphorylation and a non-canonical polycomb subcomplex.

Conclusions:

  • AR reprogramming drives prostate cancer plasticity and resistance.
  • EZH2 plays a critical role in maintaining this adaptive state.
  • Modulating EZH2 and AR offers potential for reversing resistance phenotypes and redirecting cell fate.

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