Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy.
Upregulation of constitutively-active androgen receptor splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and ARv567es, two major AR-Vs, both facilitated AR-FL nuclear localization in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, ARv567es levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a "rheostat" to control the degree of response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA.
Bo
B
Cao
Yanfeng
Y
Qi
Guanyi
G
Zhang
Duo
D
Xu
Yang
Y
Zhan
Xavier
X
Alvarez
Zhiyong
Z
Guo
Xueqi
X
Fu
Stephen R
SR
Plymate
Oliver
O
Sartor
Haitao
H
Zhang
Yan
Y
Dong
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms; D021381:Protein Transport / Q000187:drug effects; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D000728:Androgens; D001549:Benzamides; D009570:Nitriles; D020033:Protein Isoforms; D012333:RNA, Messenger; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide