Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Constitutively active androgen receptor splice variants (AR-Vs) are key drivers in castration-resistant prostate cancer (CRPC).
• AR-Vs mediate resistance to androgen-axis targeted therapies.
• The precise mechanisms of AR-V-mediated gene regulation remain largely unknown.

Purpose of the Study:

• To elucidate the dimerization capabilities of major AR-Vs (AR-V7 and AR(v567es)).
• To investigate the role of AR-V dimerization in gene transactivation and CRPC progression.
• To identify potential therapeutic targets for disrupting AR-V signaling.

Main Methods:

• Investigated homodimerization and heterodimerization of AR-V7 and AR(v567es) with each other and with full-length AR (AR-FL).
• Analyzed the molecular domains involved in AR-V and AR-FL interactions.
• Assessed the functional consequences of AR-V dimerization on target gene transactivation and cell growth.

Main Results:

• AR-V7 and AR(v567es) homodimerize and heterodimerize with each other and with AR-FL in an androgen-independent manner.
• Heterodimerization involves N- and C-terminal interactions and the DNA-binding domain; homodimerization relies solely on the DNA-binding domain.
• AR-V dimerization is essential for transactivating target genes and promoting castration-resistant cell growth.

Conclusions:

• AR-V dimerization is a critical mechanism for AR-V-mediated gene regulation in prostate cancer.
• Disrupting AR-V dimerization presents a promising therapeutic strategy for advanced prostate cancer.
• This study provides a mechanistic basis for developing novel drugs targeting AR-V signaling pathways.