Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer
MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.
|Authors||Wiklund, E.D., Bramsen, J.B., Hulf, T., Dyrskji?1/2t, L., Ramanathan, R., Hansen, T.B., Villadsen, S.B., Gao, S., Ostenfeld, M.S., Borre, M., Peter, M.E., i?1/2rntoft, T.F., Kjems, J.; Clark, S.J.|
|Publisher Name||INTERNATIONAL JOURNAL OF CANCER|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/20473948|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10419|