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Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer

Lookup NU author(s): Dr Dominic Jones, Professor Martin Noble, Professor Steve Wedge, Professor Craig Robson, Dr Luke Gaughan

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


Abstract

Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced. Critically, these effects are reproduced by Aurora A inhibition. We show that Aurora A levels increase in advanced disease and AURKA is an AR-V target gene demonstrating a positive feedback mechanism of androgenic signalling in CRPC. In all, our data suggests that Aurora A plays a pivotal role in regulation of AR-V7 expression and represents a new therapeutic target in CRPC.


Publication metadata

Author(s): Jones D, Noble M, Wedge SR, Robson CN, Gaughan L

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Online publication date: 16/02/2017

Acceptance date: 13/12/2016

Date deposited: 12/04/2017

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/srep40957

DOI: 10.1038/srep40957


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