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

Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naive-advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq datasets and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity and that this repressive function could be pathologically abrogated by AR variants in PCa.

Automated summary

Androgen receptor (AR) signaling is a key therapeutic target for hormone-naive-advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recent studies have identified constitutively active AR variants in CRPC, which lack the ligand-binding domain. These variants contribute to tumor progression by affecting gene expression. However, the specific mechanism of action of these variants compared to wild-type AR (AR-WT) remains unclear. Transcriptome analysis and functional enrichment analysis revealed that AR-WT has a transcriptional repression function associated with genes involved in cell adhesion and epithelial-to-mesenchymal transition. This repression function is pathologically lost in AR variants found in PCa.