title: The tumor suppressive miR-200b subfamily is an ERG target gene in human prostate tumors.
abstract: The TMPRSS2-ERG fusion occurs in approximately 50% of prostate cancer (PCa), resulting in expression of the oncogenic ERG in the prostate. Because ERG is a transcriptional activator, we hypothesized that ERG-regulated genes contribute to PCa development. Since microRNA (miRNA) has crucial functions in cancer, we searched for miRNAs regulated by ERG in PCas. We mined published datasets based on the MSKCC Prostate Oncogene Project, in which a comprehensive analysis defined the miRNA transcriptomes in 113 PCas. We retrieved the miRNA expression datasets, and identified miRNAs differentially expressed between ERG-positive and ERG-negative samples. Out of 369 miRNAs, miR-200a, -200b, -429 and -205 are the only miRNAs significantly increased in ERG-positive tumors. Strikingly, miR-200a, -200b and -429 are transcribed as a single polycistronic transcript, suggesting they are regulated at the transcriptional level. With ChIP-qPCR and in vitro binding assay, we identified two functional ETS motifs in the miR-200b/a/429 gene promoter. Knockdown of ERG in PCa cells reduced expression of these three miRNAs. In agreement with the well-established tumor suppressor function, overexpression of the miR-200b/a/429 gene inhibited PCa cell growth and invasion. In summary, our study reveals that miR-200b/a/429 is an ERG target gene, which implicates an important role in TMPRSS2/ERG-dependent PCa development. Although induction of the tumor suppressive miR-200b subfamily by oncogenic ERG appears to be counterintuitive, it is consistent with the observation that the vast majority of primary prostate cancers are slow-growing and indolent.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.affiliation: Department of Medicine-Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Hartig
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.|Department of Medicine-Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000071230:Transcriptional Regulator ERG / Q000235:genetics; D014162:Transfection
chemical_list: C072312:ERG protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D000071230:Transcriptional Regulator ERG
keywords: ERG; miR-200; miR-205; prostate cancer