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

Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced ‘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 wer...

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Autores principales: Fletcher, Claire E., Sulpice, Eric, Combe, Stephanie, Shibakawa, Akifumi, Leach, Damien A., Hamilton, Mark P., Chrysostomou, Stelios L., Sharp, Adam, Welti, Jon, Yuan, Wei, Dart, Dafydd. A., Knight, Eleanor, Ning, Jian, Francis, Jeffrey C., Kounatidou, Evangelia E., Gaughan, Luke, Swain, Amanda, Lupold, Shawn E., de Bono, Johann S., McGuire, Sean E., Gidrol, Xavier, Bevan, Charlotte L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755970/
https://www.ncbi.nlm.nih.gov/pubmed/31043708
http://dx.doi.org/10.1038/s41388-019-0823-5
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author Fletcher, Claire E.
Sulpice, Eric
Combe, Stephanie
Shibakawa, Akifumi
Leach, Damien A.
Hamilton, Mark P.
Chrysostomou, Stelios L.
Sharp, Adam
Welti, Jon
Yuan, Wei
Dart, Dafydd. A.
Knight, Eleanor
Ning, Jian
Francis, Jeffrey C.
Kounatidou, Evangelia E.
Gaughan, Luke
Swain, Amanda
Lupold, Shawn E.
de Bono, Johann S.
McGuire, Sean E.
Gidrol, Xavier
Bevan, Charlotte L.
author_facet Fletcher, Claire E.
Sulpice, Eric
Combe, Stephanie
Shibakawa, Akifumi
Leach, Damien A.
Hamilton, Mark P.
Chrysostomou, Stelios L.
Sharp, Adam
Welti, Jon
Yuan, Wei
Dart, Dafydd. A.
Knight, Eleanor
Ning, Jian
Francis, Jeffrey C.
Kounatidou, Evangelia E.
Gaughan, Luke
Swain, Amanda
Lupold, Shawn E.
de Bono, Johann S.
McGuire, Sean E.
Gidrol, Xavier
Bevan, Charlotte L.
author_sort Fletcher, Claire E.
collection PubMed
description Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced ‘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 markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and 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 6.9 kb 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.
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spelling pubmed-67559702019-09-24 Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer Fletcher, Claire E. Sulpice, Eric Combe, Stephanie Shibakawa, Akifumi Leach, Damien A. Hamilton, Mark P. Chrysostomou, Stelios L. Sharp, Adam Welti, Jon Yuan, Wei Dart, Dafydd. A. Knight, Eleanor Ning, Jian Francis, Jeffrey C. Kounatidou, Evangelia E. Gaughan, Luke Swain, Amanda Lupold, Shawn E. de Bono, Johann S. McGuire, Sean E. Gidrol, Xavier Bevan, Charlotte L. Oncogene Article Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced ‘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 markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and 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 6.9 kb 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. Nature Publishing Group UK 2019-05-01 2019 /pmc/articles/PMC6755970/ /pubmed/31043708 http://dx.doi.org/10.1038/s41388-019-0823-5 Text en © 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/.
spellingShingle Article
Fletcher, Claire E.
Sulpice, Eric
Combe, Stephanie
Shibakawa, Akifumi
Leach, Damien A.
Hamilton, Mark P.
Chrysostomou, Stelios L.
Sharp, Adam
Welti, Jon
Yuan, Wei
Dart, Dafydd. A.
Knight, Eleanor
Ning, Jian
Francis, Jeffrey C.
Kounatidou, Evangelia E.
Gaughan, Luke
Swain, Amanda
Lupold, Shawn E.
de Bono, Johann S.
McGuire, Sean E.
Gidrol, Xavier
Bevan, Charlotte L.
Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
title Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
title_full Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
title_fullStr Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
title_full_unstemmed Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
title_short Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
title_sort androgen receptor-modulatory micrornas provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755970/
https://www.ncbi.nlm.nih.gov/pubmed/31043708
http://dx.doi.org/10.1038/s41388-019-0823-5
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