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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Bibliographic Details
Published in:	Oncogene Vol. 38; no. 28; pp. 5700 - 5724
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2019 Nature Publishing Group Nature Publishing Group [1987-....]
Subjects:	3' Untranslated Regions 38 38/47 38/77 42/44 42/70 42/89 631/337/384 631/67/589/466 82/80 96 96/106 96/2 Analysis Androgen receptors Androgens Antisense Elements (Genetics) Apoptosis Benzamides Cell Biology Cell cycle Cell Line, Tumor Cell proliferation Development and progression DNA biosynthesis DNA repair Drug Resistance, Neoplasm Drug therapy Epithelial-Mesenchymal Transition Genetic aspects Human Genetics Humans Immune response Internal Medicine Life Sciences Male Medicine Medicine & Public Health Metastases MicroRNA MicroRNAs MicroRNAs - antagonists & inhibitors MicroRNAs - genetics MicroRNAs - physiology miRNA Neoplasm Invasiveness Neoplasm Metastasis Nitriles Oncology Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - pharmacology Pheochromocytoma cells Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - pathology Receptors, Androgen - physiology Signal Transduction Therapeutic applications Transcription Treatment outcome Tumors Xenografts
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC6755970
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-019-0823-5