Micro-RNA-204 Participates in TMPRSS2/ERG Regulation and Androgen Receptor Reprogramming in Prostate Cancer

• Published in: Hormones & cancer 2017-02, Vol.8 (1), p.28-48
• Main Authors: Todorova, Krassimira, Metodiev, Metodi V., Metodieva, Gergana, Mincheff, Milcho, Fernández, Nelson, Hayrabedyan, Soren
• Format: Article
• Language: English
• Subjects: Cell Biology; Cell Line, Tumor; Core Binding Factor Alpha 1 Subunit - metabolism; DNA Methylation; Endocrinology; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Microbiology; MicroRNAs - metabolism; Oncogene Proteins, Fusion - metabolism; Oncology; Original Paper; Promoter Regions, Genetic - genetics; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Proteomics; Proto-Oncogene Mas; Proto-Oncogene Protein c-ets-1 - metabolism; Receptors, Androgen - metabolism; Serine Endopeptidases - genetics; Signal Transduction; Systems Biology; Transcriptional Regulator ERG - genetics
• ISSN: 1868-8497; 1868-8500
• DOI: 10.1007/s12672-016-0279-9

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.