Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression
Metrics: HTML 1958 views | ?
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
Holger Sültmann, email: firstname.lastname@example.org
Keywords: miR-375, CBX7, biomarker, prostate cancer, Ago-RIP-Seq
Received: February 08, 2016 Accepted: July 09, 2016 Published: July 20, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.