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.
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Acknowledgements
The YAP1 3′-UTR plasmids were a kind gift from Prof Takashi Takahashi, Nagoya University. The results published here are in part based on the data generated by The Cancer Genome Atlas, established by the National Cancer Institute and the National Human Genome Research Institute, and we are grateful to the specimen donors and relevant research groups associated with this project. We also acknowledge the ENCODE Consortium and the Myers laboratory at the HudsonAlpha Institute for Biotechnology for generating the ZEB1 ChIP-seq data set used in this study. This work was supported by: Young Investigator Awards from the Prostate Cancer Foundation (the Foundation 14 award; LAS) and the Prostate Cancer Foundation of Australia (PCFA)/Movember (YI 0810; LAS, YI 0412; MMC) and grants from PCFA/Movember/Cancer Australia (Grant IDs 1012337 and 1043482; WDT, LAS and LMB) and the National Health and Medical Research Council (Grant ID 1083961). PAG is supported by a Beat Cancer Project fellowship from the Cancer Council of South Australia. BGH is supported by a Queensland government Smart Futures Fund Fellowship. The research programs of LAS, MMC, LMB, CCN, BGH and WDT are supported by the Movember Foundation and the Prostate Cancer Foundation of Australia through Movember Revolutionary Team Awards.
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Selth, L., Das, R., Townley, S. et al. A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer. Oncogene 36, 24–34 (2017). https://doi.org/10.1038/onc.2016.185
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DOI: https://doi.org/10.1038/onc.2016.185
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