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Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer

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Title: Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
Authors: Fletcher, C
Sulpice, E
Combe, S
Shibakawa, A
Leach, D
Hamilton, MP
Chrysostomou, SL
Sharp, A
Welti, J
Yuan, W
Dart, D
Knight, E
Ning, J
Francis, JC
Kounatidou, EE
Gaughan, L
Swain, A
Lupold, SE
De Bono, JS
McGuire, SE
Gidrol, X
Bevan, C
Item Type: Journal Article
Abstract: Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even inadvanced ‘castrate-resistant’ disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity in lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were transfected with a miR inhibitor library; 78 inhibitors significantly altered AR activity. Upon validation, miR-346, miR-361-3p and miR-197 inhibitors dramatically reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs increased AR activity through a novel and anti-dogmatic mechanism of direct association with AR 6.9kb 3’UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels of constitutively-active AR variants, and inhibited variant-driven PC cell proliferation, so may contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway analysis of AGO-PAR-CLIP-identified miR targets revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance. MiR-346 additionally upregulated the oncogene, YWHAZ, which correlated with grade, biochemical relapse and metastasis in patients. These AR-modulatory miRs and targets correlated with AR activity in patient biopsies, and were elevated in response to long-term enzalutamide treatment of patient-derived CRPC xenografts. In summary, we identified miRs that modulate AR activity in PC and CRPC, via novel mechanisms, and may represent novel PC therapeutic targets.
Issue Date: 11-Jul-2019
Date of Acceptance: 5-Feb-2019
URI: http://hdl.handle.net/10044/1/68572
DOI: 10.1038/s41388-019-0823-5
ISSN: 0950-9232
Publisher: Springer Nature [academic journals on nature.com]
Start Page: 5700
End Page: 5724
Journal / Book Title: Oncogene
Volume: 38
Issue: 28
Copyright Statement: © The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Prostate Cancer UK
Cancer Research UK
Prostate Cancer Foundation
AstraZeneca UK Limited
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: DCSJDBAAJ
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-05-01
Appears in Collections:Department of Surgery and Cancer