Oncotarget

Research Papers:

Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression

Julia M.A. Pickl, Diana Tichy, Vladimir Y. Kuryshev, Yanis Tolstov, Michael Falkenstein, Julia Schüler, Daniel Reidenbach, Agnes Hotz-Wagenblatt, Glen Kristiansen, Wilfried Roth, Boris Hadaschik, Markus Hohenfellner, Stefan Duensing, Doreen Heckmann _ and Holger Sültmann

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Oncotarget. 2016; 7:59589-59603. https://doi.org/10.18632/oncotarget.10729

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Abstract

Julia M.A. Pickl1, Diana Tichy2, Vladimir Y. Kuryshev1, Yanis Tolstov3, Michael Falkenstein3, Julia Schüler4, Daniel Reidenbach1, Agnes Hotz-Wagenblatt5, Glen Kristiansen6, Wilfried Roth7, Boris Hadaschik8, Markus Hohenfellner8, Stefan Duensing3, Doreen Heckmann1, Holger Sültmann1

1Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

2Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

3Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany

4Oncotest GmbH, Institute for Experimental Oncology, Freiburg, Germany

5Bioinformatics Group, Core Facility Genomics & Proteomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

6Institute of Pathology, Center for Integrated Oncology, University of Bonn, Bonn, Germany

7NCT Tissue Bank of The National Center of Tumor Diseases (NCT) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

8Department of Urology, University Hospital Heidelberg, Heidelberg, Germany

Correspondence to:

Holger Sültmann, email: h.sueltmann@dkfz.de

Keywords: miR-375, CBX7, biomarker, prostate cancer, Ago-RIP-Seq

Received: February 08, 2016    Accepted: July 09, 2016    Published: July 20, 2016

ABSTRACT

Prostate cancer is a heterogeneous disease. MiR-375 is a marker for prostate cancer progression, but its cellular function is not characterized. Here, we provide the first comprehensive investigation of miR-375 in prostate cancer. We show that miR-375 is enriched in prostate cancer compared to normal cells. Furthermore, miR-375 enhanced proliferation, migration and invasion in vitro and induced tumor growth and reduced survival in vivo showing that miR-375 has oncogenic properties in prostate cancer. On the molecular level, we provide the targetome and genome-wide transcriptional changes of miR-375 expression by applying a generalized linear model for Ago-RIP-Seq and RNA-Seq, and show that miR-375 is involved in tumorigenic networks and Polycomb regulation. Integration of tissue and gene ontology data prioritized miR-375 targets and identified the tumor suppressor gene CBX7, a member of Polycomb repressive complex 1, as a major miR-375 target. MiR-375-mediated repression of CBX7 was accompanied by increased expression of its homolog CBX8 and activated transcriptional programs linked to malignant progression in prostate cancer cells. Tissue analysis showed association of CBX7 loss with advanced prostate cancer. Our study indicates that miR-375 exerts its tumor-promoting role in prostate cancer by influencing the epigenetic regulation of transcriptional programs through its ability to directly target the Polycomb complex member CBX7.


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