Related Experiment Video

Updated: Sep 25, 2025

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
10:38

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture

Published on: November 22, 2019

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ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate

Shaghayegh Nouruzi1,2, Dwaipayan Ganguli2, Nakisa Tabrizian1,2

  • 1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.

Nature Communications
|April 28, 2022
PubMed

Insights

Androgen receptor pathway inhibitors (ARPIs) in prostate cancer cause neuroendocrine differentiation. Targeting ASCL1 reverses this, restoring the luminal state and ARPI sensitivity.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Androgen receptor pathway inhibitors (ARPIs) are used for prostate cancer treatment.
  • ARPIs can lead to treatment resistance via lineage plasticity and neuroendocrine differentiation.

Purpose of the Study:

  • Investigate the epigenetic mechanisms driving ARPI resistance.
  • Identify therapeutic targets to reverse neuroendocrine prostate cancer phenotype.

Main Methods:

  • Analyzed chromatin accessibility and gene expression changes induced by ARPIs.
  • Utilized transcription factor motif enrichment analysis.
  • Investigated the role of ASCL1 and the UHRF1/AMPK axis in chromatin remodeling.

Main Results:

  • ARPIs induce rapid chromatin remodeling, activating stem/neuronal programs.
  • ASCL1 is a key driver of neuroendocrine differentiation and ARPI resistance.
  • Targeting ASCL1 promotes luminal epithelial state conversion and re-sensitization to ARPIs.
  • Disruption of polycomb repressive complex-2 via UHRF1/AMPK modulates chromatin architecture.

Conclusions:

  • ARPIs induce ASCL1-governed epigenetic alterations driving neuroendocrine prostate cancer.
  • Targeting ASCL1 offers a strategy to reverse neuroendocrine phenotype and restore ARPI sensitivity.

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