1 Department of Molecular Biology, Faculty of Science, Aarhus University, Aarhus University2 Department of Molecular Biology and Genetics, Science and Technology, Aarhus University3 Department of Molecular Biology and Genetics, Science and Technology, Aarhus University
MicroRNAs (miRNA) are small non-coding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are encoded in three separate genomic loci and are frequently silenced in advanced cancer. The miR-200 family and miR-205 have been implicated in tumour invasion and metastasis by negatively regulating the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. Loss of miR-200 expression leads to silencing of E-cadherin, thereby promoting epithelial to mesenchymal transition (EMT) and loss of cell adhesion. However, little is known about the transcriptional regulation of the miR-200s. Here we show that the three miR-200 loci are concurrently silenced and gain promoter hypermethylation in muscle invasive bladder tumors and undifferentiated bladder cell lines. Furthermore, we report that the mesoderm transcription factor Twist1 and miR-200 expression is inversely correlated, and that Twist1 represses miR-200 expression in the normal bladder cell line HU609 by directly binding to E-box motifs in the miR-200 family and miR-205 promoters. This is the first implication of a role for Twist1 in transcriptional repression of miRNAs and the first report demonstrating concerted transcriptional regulation of the three miR-200 loci. Our data also indicate that DNA hypermethylation of the miR-200 family and miR-205 are possible prognostic markers in bladder cancer.
Main Research Area:
<strong><strong>Keystone Symposia - RNA Silencing: Mechanism, Biology and Application</strong></strong>, 2010