title: Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression.
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.
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Julia M A
authors.initials: JM
authors.lastname: Pickl
authors.affiliation: Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Tichy
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Kuryshev
authors.affiliation: Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Yanis
authors.initials: Y
authors.lastname: Tolstov
authors.affiliation: Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Falkenstein
authors.affiliation: Oncotest GmbH, Institute for Experimental Oncology, Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reidenbach
authors.affiliation: Bioinformatics Group, Core Facility Genomics & Proteomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Hotz-Wagenblatt
authors.affiliation: Institute of Pathology, Center for Integrated Oncology, University of Bonn, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: NCT Tissue Bank of The National Center of Tumor Diseases (NCT) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.affiliation: Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Hadaschik
authors.affiliation: Department of Urology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Heckmann
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; C503627:CBX7 protein, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D063150:Polycomb Repressive Complex 1
keywords: Ago-RIP-Seq; CBX7; biomarker; miR-375; prostate cancer