Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor variants (AR-Vs) lack the ligand-binding domain and are constitutively active transcription factors.
• AR-V expression in prostate cancer (PCa) correlates with endocrine therapy resistance and poor patient outcomes.
• Understanding AR-V chromatin binding mechanisms is crucial for identifying therapeutic vulnerabilities.

Purpose of the Study:

• To investigate the mechanisms governing AR-V chromatin binding.
• To identify potential therapeutic targets for inhibiting AR-V activity in PCa.

Main Methods:

• Chromatin immunoprecipitation and sequencing (ChIP-seq) to map AR-V binding sites.
• Biochemical experiments to assess AR-V DNA binding requirements.
• In vitro and in vivo studies using prostate cancer cell models and BET inhibitor JQ1.

Main Results:

• AR-Vs bind to canonical androgen response elements (AREs), similar to the full-length androgen receptor (AR), but with lower affinity.
• AR-V dimerization is essential for constitutive DNA binding and transcriptional activation.
• JQ1 treatment inhibited AR-V chromatin binding, reduced AR-V expression (transcript and protein), and impaired PCa cell growth.
• AR-Vs restore AR chromatin binding events suppressed by endocrine therapy.

Conclusions:

• AR-Vs broadly re-establish AR chromatin binding suppressed during endocrine therapy.
• BET inhibition, specifically with JQ1, represents a promising pre-clinical strategy to target AR-V expression and chromatin binding in PCa.