Unknown,Transcriptomics,Genomics,Proteomics

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DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer

ABSTRACT: Epithelial-to-Mesenchymal Transition (EMT) is involved in prostate cancer metastatic progression and its plasticity suggests epigenetic implications. Deregulation of UHRF1/DNMT1, DNMT3A and miRNAs play a role in EMT, but their interplay has not been clarified yet. Here, we identify miR-720 and miR-1260a as new DNMT3A regulators through miRNA microarray performed on UHRF1 silenced Androgen Receptor (AR) non-responsive (PC3) cell extracts, and subsequent target validation and functional overexpression and downregulation in PC3 and AR responsive LNCaP cells, respectively. These miRNAs inversely correlated with DNMT3A in our ex-vivo model of EMT in PC3 but not in LNCaP cells, induced with conditioned media from patient-derived Cancer-Associated Fibroblasts (CM-CAF). miR-720 and miR-1260a were expressed in very few patients from the PRAD TCGA data set expressing an EMT or MET (Mesenchymal-to-Epitelial Transition) signature; miR-200 family (miR-200a/b, -141, -429), along with miR-205 and miR-203, were downregulated in EMT patients as they modulate key EMT factors. These latter miRNAs resulted hyper-methylated at their promoters in our ex-vivo EMT prostate cancer model, while in the EMT PRAD TCGA data set only miR200c and miR141 promoters displayed a diffused hyper-methylated pattern inversely correlated with their transcriptional expression. Chromatin immunoprecipitation experiments performed on CM-CAF induced PC3 cells extracts showed that DNMT3A gets recruited onto the promoters of the latter two miRNAs, coupled with a marked increase of H3K27me3 and H3K9me3 and/or the decrease of H3K4me3 and H3K36me3. Altogether, our results point to a DNMT3A regulatory role of key miRNAs for EMT in prostate cancer.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Homo sapiens

SUBMITTER: Giorgio Giurato

PROVIDER: E-MTAB-9835 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA) -related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) in NSCLC. MiRNA expression profiles were examined before and after transforming growth factor-beta1 (TGF-M-NM-21) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. MiRNA array and quantitative RT-PCR revealed that TGF-M-NM-21 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN (phosphatase and tensin homolog), was diminished in A549 cells with EMT after the TGF-M-NM-21 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-M-NM-21-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-M-NM-21-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, whose suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be new therapeutic targets in advanced lung adenocarcinoma patients, depending on the EMT phenomenon. miRNA expression profiles before and after TGF-M-NM-21 exposure were assessed in the four lung adenocarcinoma cell lines, A549, LC2/ad, PC3, and, PC9 by TaqMan miRNA arrays. Relative ratios of miRNAs in cells after TGF-M-NM-21 exposure were calculated when compared with the cells before TGF-M-NM-21 exposure.

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DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer

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