A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer.
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.
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Selth
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Das
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Townley
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Coutinho
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Hanson
Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
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Centenera
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
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Stylianou
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
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Sweeney
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
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Soekmadji
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
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Jovanovic
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
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Nelson
The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Australia.
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Zoubeidi
Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
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Butler
Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.|School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
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Goodall
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
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Hollier
Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
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Gregory
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
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Tilley
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D019859:Proto-Oncogene Proteins c-met