Related Experiment Video

Updated: May 22, 2025

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
12:13

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients

Published on: November 19, 2019

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Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells

Shan Lu1, Zhongyun Dong1

  • 1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

Oncotarget
|May 20, 2025
PubMed

Insights

Targeting the interaction between proliferating cell nuclear antigen (PCNA) and androgen receptor (AR) inhibits prostate cancer growth. This novel strategy targets both full-length and variant AR signaling, offering a new therapeutic approach for castration-resistant prostate cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Proliferating cell nuclear antigen (PCNA) interacts with androgen receptor (AR) via PIP-box4, regulating AR activity.
  • Androgen receptor (AR) signaling is a key driver in prostate cancer progression, particularly in castration-resistant prostate cancer (CRPC).

Purpose of the Study:

  • To investigate the PCNA/AR interaction further, identify new binding sites, and evaluate targeting this interaction as a therapeutic strategy for CRPC.
  • To assess the impact of inhibiting PCNA/AR interaction on AR transcriptional activity and downstream gene expression in CRPC models.

Main Methods:

  • Identification of a second PIP-box (PIP-box592) in the AR DNA binding domain.
  • Treatment of AR-positive CRPC cells with R9-AR-PIP (a PIP-box4-mimicking peptide) and PCNA-I1S (a small molecule PCNA inhibitor).
  • Assessment of AR occupancy at androgen response elements (AREs), target gene expression, transcriptional activity, and cytotoxicity.

Main Results:

  • Dihydrotestosterone enhances AR-FL binding to PCNA, but not AR-V7.
  • R9-AR-PIP inhibits PCNA/AR interaction, AR occupancy at AREs in PSA and p21 genes, and AR target gene expression, leading to CRPC cell cytotoxicity.
  • Both R9-AR-PIP and PCNA-I1S inhibit AR occupancy at the CCNA2 gene ARE and cyclin A2 expression; cyclin A2 is overexpressed in CRPC cells.

Conclusions:

  • Targeting the PCNA/AR interaction effectively inhibits both AR-FL and AR-V signaling pathways.
  • Inhibition of PCNA/AR interaction represents a promising novel therapeutic strategy for castration-resistant prostate cancer.
  • Overexpression of cyclin A2 in CRPC suggests its potential role in disease development and as a therapeutic target.
Keywords:
AR splicing variantsCRPCPCNAPCNA inhibitorsandrogen receptor

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