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

L. A. Selth, R. Das, S. L. Townley, I. Coutinho, A. R. Hanson, M. M. Centenera, N. Stylianou, K. Sweeney, C. Soekmadji, L. Jovanovic, C. C. Nelson, A. Zoubeidi, L. M. Butler, G. J. Goodall, B. G. Hollier, P. A. Gregory, W. D. Tilley

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54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24-34
Number of pages11
JournalOncogene
Volume36
Early online date6 Jun 2016
DOIs
Publication statusPublished - 5 Jan 2017
Externally publishedYes

Keywords

  • MicroRNA-375
  • prostate tumors
  • prostate cancer

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    Selth, L. A., Das, R., Townley, S. L., Coutinho, I., Hanson, A. R., Centenera, M. M., Stylianou, N., Sweeney, K., Soekmadji, C., Jovanovic, L., Nelson, C. C., Zoubeidi, A., Butler, L. M., Goodall, G. J., Hollier, B. G., Gregory, P. A., & Tilley, W. D. (2017). A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer. Oncogene, 36, 24-34. https://doi.org/10.1038/onc.2016.185