title: Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer.
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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Ne2 4HH, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Jones
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Ne2 4HH, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Noble
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Ne2 4HH, UK.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Wedge
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Ne2 4HH, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Ne2 4HH, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000096:biosynthesis*
chemical_list: D011944:Receptors, Androgen; C576917:AURKA protein, human; D064096:Aurora Kinase A