title: Micro-RNA-204 Participates in TMPRSS2/ERG Regulation and Androgen Receptor Reprogramming in Prostate Cancer.
abstract: Cancer progression is driven by genome instability incurred rearrangements such as transmembrane protease, serine 2 (TMPRSS2)/v-ets erythroblastosis virus E26 oncogene (ERG) that could possibly turn some of the tumor suppressor micro-RNAs into pro-oncogenic ones. Previously, we found dualistic miR-204 effects, acting either as a tumor suppressor or as an oncomiR in ERG fusion-dependent manner. Here, we provided further evidence for an important role of miR-204 for TMPRSS2/ERG and androgen receptor (AR) signaling modulation and fine tuning that prevents TMPRSS2/ERG overexpression in prostate cancer. Based on proximity-based ligation assay, we designed a novel method for detection of TMPRSS2/ERG protein products. We found that miR-204 is TMPRSS2/ERG oncofusion negative regulator, and this was mediated by DNA methylation of TMPRSS2 promoter. Transcriptional factors runt-related transcription factor 2 (RUNX2) and ETS proto-oncogene 1 (ETS1) were positive regulators of TMPRSS2/ERG expression and promoter hypo-methylation. Clustering of patients' sera for fusion protein, transcript expression, and wild-type ERG transcript isoforms, demonstrated not all patients harboring fusion transcripts had fusion protein products, and only few fusion positive ones exhibited increased wild-type ERG transcripts. miR-204 upregulated AR through direct promoter hypo-methylation, potentiated by the presence of ERG fusion and RUNX2 and ETS1. Proteomics studies provided evidence that miR-204 has dualistic role in AR cancer-related reprogramming, promoting prostate cancer-related androgen-responsive genes and AR target genes, as well as AR co-regulatory molecules. miR-204 methylation regulation was supported by changes in molecules responsible for chromatin remodeling, DNA methylation, and its regulation. In summary, miR-204 is a mild regulator of the AR function during the phase of preserved AR sensitivity as the latter one is required for ERG-fusion translocation.
authors.affiliation: Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Laboratory of Reproductive OMICs Technologies, Bulgarian Academy of Sciences, 73 Tsarigradsko shosse blvd, 1113, Sofia, Bulgaria.
authors.forename: Krassimira
authors.initials: K
authors.lastname: Todorova
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, UK.
authors.forename: Metodi V
authors.initials: MV
authors.lastname: Metodiev
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, UK.
authors.forename: Gergana
authors.initials: G
authors.lastname: Metodieva
authors.affiliation: Cellular and Gene Therapy Ward, National Specialized Hematology Hospital, Sofia, Bulgaria.
authors.forename: Milcho
authors.initials: M
authors.lastname: Mincheff
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, UK.
authors.forename: Nelson
authors.initials: N
authors.lastname: Fernández
authors.affiliation: Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Laboratory of Reproductive OMICs Technologies, Bulgarian Academy of Sciences, 73 Tsarigradsko shosse blvd, 1113, Sofia, Bulgaria. shayrabedyan@ibir.bas.bg.
authors.forename: Soren
authors.identifier: http://orcid.org/0000-0002-2147-1982
authors.initials: S
authors.lastname: Hayrabedyan
mesh_terms: D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics; D015398:Signal Transduction; D000071230:Transcriptional Regulator ERG / Q000235:genetics
chemical_list: C410798:AR protein, human; D050659:Core Binding Factor Alpha 1 Subunit; C072312:ERG protein, human; C494041:ETS1 protein, human; C000715470:MAS1 protein, human; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; C493709:RUNX2 protein, human; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human