Related Experiment Video

Updated: Nov 12, 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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A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

Yundong He1, Ting Wei2, Zhenqing Ye2

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Nature Communications
|March 22, 2021
PubMed

Insights

Enzalutamide resistance in prostate cancer involves new androgen receptor binding sites. Targeting CXXC5 and BET/CBP/p300 proteins offers a novel therapeutic strategy for castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Enzalutamide (ENZ) resistance is a significant hurdle in treating castration-resistant prostate cancer (CRPC).
  • Understanding the molecular mechanisms underlying ENZ resistance is crucial for developing effective therapies.

Purpose of the Study:

  • To identify novel mechanisms of androgen receptor (AR) binding and gene regulation in ENZ-resistant CRPC.
  • To explore potential therapeutic targets for overcoming ENZ resistance.

Main Methods:

  • Genome-wide ChIP-seq profiling to identify AR binding sites in ENZ-resistant CRPC cells.
  • RNA-seq analysis to assess gene expression changes.
  • Validation in patient-derived xenografts (PDXs) and patient specimens.

Main Results:

  • Identified "ARBS-gained" loci with increased AR binding intensity, lacking canonical elements but enriched for CpG islands, CXXC5, and TET2.
  • CXXC5 and its target gene ID1 were upregulated in ENZ-resistant models.
  • ENZ-resistant cells showed hyper-sensitivity to NEO2734, a BET and CBP/p300 inhibitor, correlating with H3K27ac modification at ARBS-gained loci.

Conclusions:

  • Revealed a noncanonical AR function in the development of ENZ resistance.
  • Suggests targeting CXXC5 and BET/CBP/p300 pathways as a potential therapeutic strategy for ENZ-resistant CRPC.

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