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

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.

• Authors: 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
• Journal: Cancer letters (Cancer Lett) Vol. 504 Pg. 37-48 (04 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33556543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• AR protein, human
• Androgen Antagonists
• Androgens
• RNA, Messenger
• Receptors, Androgen

Topics

• Androgen Antagonists (pharmacology)
• Androgens (deficiency)
• Humans
• Male
• Protein Biosynthesis
• RNA Splicing
• RNA, Messenger (genetics)
• Receptors, Androgen (genetics)
• Transcription, Genetic