A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer

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dc.contributor.authorSelth, L.
dc.contributor.authorDas, R.
dc.contributor.authorTownley, S.
dc.contributor.authorCoutinho, I.
dc.contributor.authorHanson, A.
dc.contributor.authorCentenera, M.
dc.contributor.authorStylianou, N.
dc.contributor.authorSweeney, K.
dc.contributor.authorSoekmadji, C.
dc.contributor.authorJovanovic, L.
dc.contributor.authorNelson, C.
dc.contributor.authorZoubeidi, A.
dc.contributor.authorButler, L.
dc.contributor.authorGoodall, G.
dc.contributor.authorHollier, B.
dc.contributor.authorGregory, P.
dc.contributor.authorTilley, W.
dc.date.issued2017
dc.description.abstractMicroRNA-375 (miR-375) is frequently elevated in prostate tumors and cell-free fractions of patient blood, but its role in genesis and progression of prostate cancer is poorly understood. In this study, we demonstrated that miR-375 is inversely correlated with epithelial–mesenchymal transition signatures (EMT) in clinical samples and can drive mesenchymal–epithelial transition (MET) in model systems. Indeed, miR-375 potently inhibited invasion and migration of multiple prostate cancer lines. The transcription factor YAP1 was found to be a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression, and overexpression of YAP1 rescued anti-invasive effects mediated by miR-375. Furthermore, transcription of the miR-375 gene was shown to be directly repressed by the EMT transcription factor, ZEB1. Analysis of multiple patient cohorts provided evidence for this ZEB1-miR-375-YAP1 regulatory circuit in clinical samples. Despite its anti-invasive and anti-EMT capacities, plasma miR-375 was found to be correlated with circulating tumor cells in men with metastatic disease. Collectively, this study provides new insight into the function of miR-375 in prostate cancer, and more broadly identifies a novel pathway controlling epithelial plasticity and tumor cell invasion in this disease.
dc.description.statementofresponsibilityLA Selth, R Das, SL Townley, I Coutinho, AR Hanson, MM Centenera, N Stylianou, K Sweeney, C Soekmadji, L Jovanovic, CC Nelson, A Zoubeidi, LM Butler, GJ Goodall, BG Hollier, PA Gregory, and WD Tilley
dc.identifier.citationOncogene, 2017; 36(1):24-34
dc.identifier.doi10.1038/onc.2016.185
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.orcidSelth, L. [0000-0002-4686-1418]
dc.identifier.orcidCentenera, M. [0000-0002-2206-0632]
dc.identifier.orcidButler, L. [0000-0003-2698-3220]
dc.identifier.orcidGoodall, G. [0000-0003-1294-0692]
dc.identifier.orcidGregory, P. [0000-0002-0999-0632]
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]
dc.identifier.urihttp://hdl.handle.net/2440/105537
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1083961
dc.rights© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved
dc.source.urihttps://doi.org/10.1038/onc.2016.185
dc.subjectEpithelium
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectProstatic Neoplasms
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectPhosphoproteins
dc.subjectTranscription Factors
dc.subjectMicroRNAs
dc.subject3' Untranslated Regions
dc.subjectSignal Transduction
dc.subjectGene Expression
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectRNA Interference
dc.subjectPhenotype
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-met
dc.subjectNeoplastic Cells, Circulating
dc.subjectEpithelial-Mesenchymal Transition
dc.subjectBiomarkers
dc.subjectZinc Finger E-box-Binding Homeobox 1
dc.subjectYAP-Signaling Proteins
dc.titleA ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer
dc.typeJournal article
pubs.publication-statusPublished

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