Increased transcription and high translation efficiency lead to accumulation of androgen receptor splice variant after androgen deprivation therapy

Tianfang Ma, Shanshan Bai, Yanfeng Qi, Yang Zhan, Nathan Ungerleider, Derek Y. Zhang, Taavi Neklesa, Eva Corey, Scott M. Dehm, Kun Zhang, Erik K. Flemington, Yan Dong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)37-48
Number of pages12
JournalCancer Letters
Volume504
DOIs
StatePublished - Apr 28 2021

Bibliographical note

Funding 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.

Publisher Copyright:
© 2021 Elsevier B.V.

Keywords

  • AR negative autoregulation
  • AR-V mRNA stability
  • AR-V protein stability
  • AR-V translation
  • Castration resistance
  • Castration-resistant prostate cancer

Fingerprint Dive into the research topics of 'Increased transcription and high translation efficiency lead to accumulation of androgen receptor splice variant after androgen deprivation therapy'. Together they form a unique fingerprint.

Cite this