Upregulation of androgen receptor splice variants (AR-Vs), especially AR-V7, is associated with castration resistance of prostate cancer. At the RNA level, AR-V7 upregulation is generally coupled with increased full-length AR (AR-FL); consequently, AR-V7 and AR-Vs collectively constitute a minority of the AR population. However, Western blotting showed that the relative abundance of AR-V proteins is much higher in many castration-resistant prostate cancers (CRPCs). To address the mechanism underlying this discrepancy, we analyzed RNA-seq data from ~350 CRPC samples and found a positive correlation between all canonical and alternative AR splicing. This indicates that increased alternative splicing is not at the expense of canonical splicing. Instead, androgen deprivation releases AR-FL from repressing the transcription of the AR gene to induce coordinated increase of AR-FL and AR-V mRNAs. At the protein level, however, androgen deprivation induces AR-FL, but not AR-V, degradation. Moreover, AR-V7 is translated much faster than AR-FL. Thus, androgen-deprivation-induced AR-gene transcription and AR-FL protein decay, together with efficient AR-V7 translation, explain the discrepancy between the relative AR-V mRNA and protein abundances in many CRPCs, highlighting the inevitability of AR-V induction after endocrine therapy.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health [grant numbers R01CA188609 , R01AI106676 , R01CA243793 , R01CA174777 , R21CA236549 , P50CA097186 , P01CA163227 , RCMI 2G12MD007595 , 5P20GM103424 ]; the Department of Defense [grant numbers W81XWH-15-1-0439 , W81XWH-16-1-0317 , W81XWH-16-1-0318 ]; and the Prostate Cancer Foundation . The Richard M Lucas Foundation supported the development of the LuCaP models.
© 2021 Elsevier B.V.
- AR negative autoregulation
- AR-V mRNA stability
- AR-V protein stability
- AR-V translation
- Castration resistance
- Castration-resistant prostate cancer