Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial-Mesenchymal Plasticity in Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Epithelial-to-mesenchymal plasticity (EMP) is implicated in cancer metastasis, stemness, and drug resistance.
• In prostate cancer, EMP's relationship with androgen receptor (AR) signaling is complex, involving both suppression and activation.
• Understanding EMP's role in prostate cancer progression and treatment response is crucial.

Purpose of the Study:

• To investigate the impact of the AR antagonist enzalutamide on EMP in prostate cancer.
• To elucidate the molecular mechanisms underlying enzalutamide-induced EMP.
• To explore the implications of these findings for prostate cancer therapy resistance.

Main Methods:

• Utilized multiple preclinical prostate cancer models and patient tissues.
• Assessed expression of EMP drivers and mesenchymal markers following enzalutamide treatment.
• Performed knockdown and overexpression studies of AR and Snail to determine their roles.
• Investigated the direct interaction between AR and the SNAI1 promoter.

Main Results:

• Enzalutamide significantly enhanced EMP drivers (ZEB1, ZEB2, Snail, Twist, FOXC2) and mesenchymal markers (N-cadherin, fibronectin, vimentin).
• Enzalutamide promoted prostate cancer cell migration and induced a fibroblast-like morphology.
• Enzalutamide-induced EMP was dependent on AR signaling suppression and Snail activation.
• AR directly repressed SNAI1 gene expression via binding to its promoter, explaining the inverse AR-Snail correlation.

Conclusions:

• Enzalutamide induces EMP in prostate cancer by de-repressing Snail through AR signaling suppression.
• This adaptive response contributes to therapy resistance in prostate cancer.
• Findings reveal a novel mechanism linking AR signaling, Snail, and EMP with therapeutic implications.