The RNA-binding protein Sam68 regulates expression and transcription function of the androgen receptor splice variant AR-V7

Stockley, J., Markert, E., Zhou, Y., Robson, C. N., Elliott, D. J., Lindberg, J., Leung, H. Y. and Rajan, P. (2015) The RNA-binding protein Sam68 regulates expression and transcription function of the androgen receptor splice variant AR-V7. Scientific Reports, 5, 13426. (doi:10.1038/srep13426) (PMID:26310125) (PMCID:PMC4550848)

[img]
Preview
Text
108819.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

Abstract

Castration-resistant (CR) prostate cancer (PCa) partly arises due to persistence of androgen receptor (AR) transcriptional activity in the absence of cognate ligand. An emerging mechanism underlying the CRPCa phenotype and predicting response to therapy is the expression of the constitutively-active AR-V7 splice variant generated by AR cryptic exon 3b inclusion. Here, we explore the role of the RNA-binding protein (RBP) Sam68 (encoded by KHDRBS1), which is over-expressed in clinical PCa, on AR-V7 expression and transcription function. Using a minigene reporter, we show that Sam68 controls expression of exon 3b resulting in an increase in endogenous AR-V7 mRNA and protein expression in RNA-binding-dependent manner. We identify a novel protein-protein interaction between Sam68 and AR-V7 mediated by a common domain shared with full-length AR, and observe these proteins in the cell nucleoplasm. Using a luciferase reporter, we demonstrate that Sam68 co-activates ligand-independent AR-V7 transcriptional activity in an RNA-binding-independent manner, and controls expression of the endogenous AR-V7-specific gene target UBE2C. Our data suggest that Sam68 has separable effects on the regulation of AR-V7 expression and transcriptional activity, through its RNA-binding capacity. Sam68 and other RBPs may control expression of AR-V7 and other splice variants as well as their downstream functions in CRPCa.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Markert, Dr Elke and Leung, Professor Hing and Elliott, Professor David and Zhou, Mr Yan and Rajan, Dr Prabhakar and Stockley, Dr Jacqueline
Authors: Stockley, J., Markert, E., Zhou, Y., Robson, C. N., Elliott, D. J., Lindberg, J., Leung, H. Y., and Rajan, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Scientific Reports 5:13426
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
595221Systems analysis of RNA-binding protein function in metastic prostate cancer.Prabhakar RajanCancer Research UK (CAN-RES-UK)15339ICS - CLINICAL TRIALS RESEARCH
595222Systems analysis of RNA-binding protein function in metastic prostate cancer.Prabhakar RajanCancer Research UK (CAN-RES-UK)15339ICS - CLINICAL TRIALS RESEARCH