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