Androgen receptor-mediated transcriptional repression targets cell plasticity in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor (AR) signaling is a critical therapeutic target for both hormone-naïve-advanced and castration-resistant prostate cancer (CRPC).
• Castration-resistant prostate cancer is characterized by constitutively active AR variants lacking the ligand-binding domain, which promote tumor progression.
• The precise functional differences between wild-type AR (AR-WT) and AR variants remain incompletely understood.

Purpose of the Study:

• To investigate the specific mode of action of AR variants compared to AR-WT.
• To identify the transcriptional functions of AR-WT that are altered in AR variants.
• To elucidate the role of AR-WT's repressive function in normal prostate epithelial cells.

Main Methods:

• Performed AR transcriptome analyses in an androgen-dependent prostate cancer cell line.
• Conducted cross-analyses with publicly available RNA-sequencing datasets.
• Utilized functional enrichment analyses to identify gene pathways associated with AR functions.

Main Results:

• Established that AR variants lose the transcriptional repression capacity characteristic of AR-WT.
• Associated AR-WT's repressive function with genes involved in cell adhesion and epithelial-to-mesenchymal transition.
• Identified a panel of genes linked to cell plasticity regulated by AR-WT.

Conclusions:

• Postulate that a normal function of AR-WT in prostate epithelial cells is the repression of genes promoting cell plasticity.
• Conclude that AR variants may pathologically abrogate this AR-WT repressive function in prostate cancer.
• Suggest that the loss of AR-WT's repressive function by AR variants contributes to prostate cancer progression.