Interplay between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediates Castration Resistance

• Published in: Molecular cancer research 2017-01, Vol.15 (1), p.59-68
• Main Authors: Zhan, Yang, Zhang, Guanyi, Wang, Xiaojie, Qi, Yanfeng, Bai, Shanshan, Li, Dongying, Ma, Tianfang, Sartor, Oliver, Flemington, Erik K, Zhang, Haitao, Lee, Peng, Dong, Yan
• Format: Article
• Language: English
• Subjects: Alternative splicing; Alternative Splicing - genetics; Androgen receptors; Androgens; Androgens - metabolism; Cancer; Castration; Cell Line, Tumor; Cell Nucleus - metabolism; Cytoplasm; HEK293 Cells; Humans; Localization; Male; Models, Biological; Nuclei; Nuclei (cytology); Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Multimerization; Protein Transport; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signaling; Transcription; Transcriptional Activation - genetics; Tumors
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-16-0236

Androgen receptor splice variants (AR-V) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often coexpressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the antiandrogen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V-specific targets and to confer castration-resistant cell growth. However, although AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration-resistant disease. This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. Mol Cancer Res; 15(1); 59-68. ©2016 AACR.