title: TMPRSS2-ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c.
abstract: Chromosomal translocations that juxtapose the androgen-sensitive transmembrane protease, serine 2 (TMPRSS2) gene promoter to the oncogenic ETS-family transcription factor ERG result in excessive ERG overexpression in approximately 50% of prostate cancer (PCa) patients. Although numerous studies have investigated ERG-downstream genes, such studies have not attempted to examine miRNAs, which however are emerging to be important regulators of cancer. Through bioinformatics analysis of ChIP-Seq ERG data and miRNA expression profiling data we nominated miR-200c as a direct target of ERG. Experimentation of PCa cells with ERG overexpression or knockdown demonstrated that ERG directly repressed miR-200c expression by physically binding to the erythroblast transformation-specific (ETS) motif within its promoter. Consequently, miR-200c was downregulated in ERG-positive PCa, and miR-200c target gene expression was restored. In addition, the expression pattern of miR-200c target genes predicted ERG status in clinical PCa specimens. Furthermore, miR-200c was found to be important in modulating ZEB1 upregulation by ERG. Most importantly, miR-200c reconstitution fully reversed ERG-induced epithelial-to-mesenchymal transition (EMT), cell migration and invasion. Therefore, our study report miR-200c as the first miRNA target of ERG and a critical inhibitor of PCa cell motility. Therapeutic delivery of miR-200c may provide personalized treatment for patients with the molecular subtype of PCa that harbors TMPRSS2-ERG gene fusions.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Zhao
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Jin
authors.affiliation: 1] Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA [2] Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1