Selth, L.Das, R.Townley, S.Coutinho, I.Hanson, A.Centenera, M.Stylianou, N.Sweeney, K.Soekmadji, C.Jovanovic, L.Nelson, C.Zoubeidi, A.Butler, L.Goodall, G.Hollier, B.Gregory, P.Tilley, W.2017-05-312017-05-312017Oncogene, 2017; 36(1):24-340950-92321476-5594http://hdl.handle.net/2440/105537MicroRNA-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.en© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reservedEpitheliumCell Line, TumorAnimalsHumansProstatic NeoplasmsAdaptor Proteins, Signal TransducingPhosphoproteinsTranscription FactorsMicroRNAs3' Untranslated RegionsSignal TransductionGene ExpressionGene Expression Regulation, NeoplasticRNA InterferencePhenotypeMaleProto-Oncogene Proteins c-metNeoplastic Cells, CirculatingEpithelial-Mesenchymal TransitionBiomarkersZinc Finger E-box-Binding Homeobox 1YAP-Signaling ProteinsJournal article003004923610.1038/onc.2016.1850003940691000032-s2.0-84976320694253827Selth, L. [0000-0002-4686-1418]Centenera, M. [0000-0002-2206-0632]Butler, L. [0000-0003-2698-3220]Goodall, G. [0000-0003-1294-0692]Gregory, P. [0000-0002-0999-0632]Tilley, W. [0000-0003-1893-2626]