Increased transcription and high translation efficiency lead to accumulation of androgen receptor splice variant after androgen deprivation therapy
| Autor: | Eva Corey, Scott M. Dehm, Yanfeng Qi, Shanshan Bai, Tianfang Ma, Derek Y. Zhang, Nathan Ungerleider, Erik K. Flemington, Kun Zhang, Yang Zhan, Yan Dong, Taavi Neklesa |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Cancer Research Transcription Genetic medicine.drug_class RNA Splicing Population Biology Article Androgen deprivation therapy 03 medical and health sciences Prostate cancer 0302 clinical medicine Downregulation and upregulation medicine Humans RNA Messenger education education.field_of_study Alternative splicing Androgen Antagonists Androgen medicine.disease Cell biology Androgen receptor 030104 developmental biology Oncology Receptors Androgen Protein Biosynthesis 030220 oncology & carcinogenesis RNA splicing Androgens |
| Zdroj: | Cancer Lett |
| ISSN: | 0304-3835 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect