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Type: Journal article
Title: A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer
Author: 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.
Citation: Oncogene, 2017; 36(1):24-34
Publisher: Nature Publishing Group
Issue Date: 2017
ISSN: 0950-9232
Statement of
LA 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
Abstract: MicroRNA-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.
Keywords: Epithelium
Cell Line, Tumor
Prostatic Neoplasms
Adaptor Proteins, Signal Transducing
Transcription Factors
3' Untranslated Regions
Signal Transduction
Gene Expression
Gene Expression Regulation, Neoplastic
RNA Interference
Proto-Oncogene Proteins c-met
Neoplastic Cells, Circulating
Epithelial-Mesenchymal Transition
Zinc Finger E-box-Binding Homeobox 1
Rights: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved
DOI: 10.1038/onc.2016.185
Grant ID:
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