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dc.contributor.authorFletcher, CE
dc.contributor.authorSulpice, E
dc.contributor.authorCombe, S
dc.contributor.authorShibakawa, A
dc.contributor.authorLeach, DA
dc.contributor.authorHamilton, MP
dc.contributor.authorChrysostomou, SL
dc.contributor.authorSharp, A
dc.contributor.authorWelti, J
dc.contributor.authorYuan, W
dc.contributor.authorDart, DA
dc.contributor.authorKnight, E
dc.contributor.authorNing, J
dc.contributor.authorFrancis, JC
dc.contributor.authorKounatidou, EE
dc.contributor.authorGaughan, L
dc.contributor.authorSwain, A
dc.contributor.authorLupold, SE
dc.contributor.authorde Bono, JS
dc.contributor.authorMcGuire, SE
dc.contributor.authorGidrol, X
dc.contributor.authorBevan, CL
dc.date.accessioned2019-07-17T08:58:37Z
dc.date.issued2019-07
dc.identifier.citationOncogene, 2019, 38 (28), pp. 5700 - 5724
dc.identifier.issn0950-9232
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3289
dc.identifier.eissn1476-5594
dc.identifier.doi10.1038/s41388-019-0823-5
dc.description.abstractAndrogen 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.
dc.formatPrint-Electronic
dc.format.extent5700 - 5724
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectProstatic Neoplasms
dc.subjectNeoplasm Invasiveness
dc.subjectNeoplasm Metastasis
dc.subjectPhenylthiohydantoin
dc.subjectReceptors, Androgen
dc.subjectAntisense Elements (Genetics)
dc.subjectMicroRNAs
dc.subject3' Untranslated Regions
dc.subjectSignal Transduction
dc.subjectDrug Resistance, Neoplasm
dc.subjectMale
dc.subjectEpithelial-Mesenchymal Transition
dc.titleAndrogen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-02-05
rioxxterms.versionofrecord10.1038/s41388-019-0823-5
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncogene
pubs.issue28
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.publication-statusPublished
pubs.volume38
pubs.embargo.termsNot known
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamTranslational Therapeuticsen_US
icr.researchteamDevelopment & Canceren_US
dc.contributor.icrauthorSharp, Adamen
dc.contributor.icrauthorSwain, Amandaen
dc.contributor.icrauthorDe Bono, Johannen


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