Interplay between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediates Castration Resistance.
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.
College of Life Sciences, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China.|Department of Structural and Cellular Biology, Tulane Cancer Center, New Orleans, Louisiana.
Yang
Y
Zhan
Department of Pathology and Laboratory Medicine, Tulane Cancer Center, New Orleans, Louisiana.
Guanyi
G
Zhang
College of Life Sciences, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China.
Xiaojie
X
Wang
Department of Structural and Cellular Biology, Tulane Cancer Center, New Orleans, Louisiana.
Yanfeng
Y
Qi
College of Life Sciences, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China.|Department of Structural and Cellular Biology, Tulane Cancer Center, New Orleans, Louisiana.
Shanshan
S
Bai
Department of Pathology and Laboratory Medicine, Tulane Cancer Center, New Orleans, Louisiana.
Dongying
D
Li
College of Life Sciences, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China.|Department of Structural and Cellular Biology, Tulane Cancer Center, New Orleans, Louisiana.
Tianfang
T
Ma
Department of Urology, Tulane Cancer Center, New Orleans, Louisiana.|Department of Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana.
Oliver
O
Sartor
Department of Pathology and Laboratory Medicine, Tulane Cancer Center, New Orleans, Louisiana.
Erik K
EK
Flemington
Department of Pathology and Laboratory Medicine, Tulane Cancer Center, New Orleans, Louisiana.
Haitao
H
Zhang
Department of Pathology, New York University School of Medicine, New York, New York. ydong@tulane.edu Peng.Lee@nyumc.org.
Peng
P
Lee
College of Life Sciences, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China. ydong@tulane.edu Peng.Lee@nyumc.org.|Department of Structural and Cellular Biology, Tulane Cancer Center, New Orleans, Louisiana.
Yan
Y
Dong
D017398:Alternative Splicing / Q000235:genetics*; D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008954:Models, Biological; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D055503:Protein Multimerization; D021381:Protein Transport; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
D000728:Androgens; D011944:Receptors, Androgen
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