Abstract 4580: A blueprint of androgen receptor splice variant transactivation

Constitutively active androgen receptor splice variants (AR-Vs) have been implicated as one driver of castration-resistant progression of prostate cancer. However, the critical steps leading to AR-V transactivation remain largely unknown. AR-V7 and ARv567es are two major AR-Vs expressed in human prostate cancer specimens. We found that disruption of AR-V7 and ARv567es homodimerization did not affect their nuclear localization, indicating that they can enter the nucleus as monomers. On the other hand, disrupting the heterodimerization between AR-V7 or ARv567es and AR-FL abolished AR-V7 and ARv567es-induced nuclear translocation of AR-FL, indicating that the heterodimerization is required for AR-FL to be piggy bagged into the nucleus. AR-V7 chromatin immunoprecipitation assay further showed that mutating the dimerization interface of AR-V7 did not decrease the ability of AR-V7 to bind to the promoter of its target genes, UBE2C and CCNA2, indicating that dimerization is not required for AR-Vs to bind to DNA. Moreover, mutating the DNA-binding interface of AR-V7 only partially inhibited AR-V7 homodimerization and had no effect on AR-FL/AR-V7 dimerization, suggesting that DNA binding may not be necessary for AR-V/AR-V or AR-FL/AR-V dimerization. Nonetheless, both the dimerization and the DNA-binding mutants of AR-V7 lost trans-activating activity. Taken together, our data suggests that AR-V DNA binding and dimerization are two independent but indispensable steps for AR-V transactivation. AR-V can enter the nucleus as a monomer, and then either forms a dimer before binding to DNA or binds to DNA as a monomer and then forms a dimer to trans-activate gene transcription. Our study may provide insights into developing more precisely targeted strategies to overcome AR-V-driven castration resistance. Citation Format: Subing Cao, Duo Xu, Yanfeng Qi, Yang Zhan, Oliver Sartor, Yan Dong. A blueprint of androgen receptor splice variant transactivation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4580.