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

Lookup NU author(s): Dr Jacqueline Stockley, Professor Craig Robson, Professor David Elliott, Professor Hing Leung, Dr Prabhakar Rajan

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Stockley J, Markert E, Zhou Y, Robson CN, Elliott DJ, Lindberg J, Leung HY, Rajan P

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2015

Volume: 5

Online publication date: 27/08/2015

Acceptance date: 27/07/2015

ISSN (print): 2045-2322

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/srep13426

DOI: 10.1038/srep13426


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