The epigenetics of EZH2-regulated microRNAs in Prostate Cancer
McLeod, Megan R.
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Prostate cancer ranks among the leading causes of death in Northem American and European male populations. Enhancer zest homologue 2 (EZH2), a highly conserved catalytic methyltransferase, is up-regulated during prostate tumorigenesis. However, EZH2 expression is only one component of the cqmplex epigenetic coordination of severa! protein products and microRNAs (miRNAs). Severa! families of miRNAs have been implicated as key components of heritable epigenetic dysregulation associated with EZH2 in prostate cancer. Here, we hypothesize that the dysregulation of severa! previously unstudied EZH2-regulated miRNAs (hsa-miR-141, hsa-miR-146 and hsamiR- 193) promotes tumorigenesis via the dysregulation of severa! oftheir targets: F box repeat containing protein 2 (FBXW2), Pleiomorphic adenoma gene 1 (PLAG 1) and 1NF receptor-associated factor 6 (TRAF6). This hypothesis implies that regulation occurs via a direct binding interaction between mRNA and miRNA resulting in mRNA degredation. We explore these questions via manipulation ofmiRNA expression and observation of target mRNA and protein expression in prostate cancer cells (DU145). Results ofinsilico analyses and mRNA expression resulting from various treatments of prostate cancer cells support our hypothesis. TRAF6 protein expression was increased, however, failing to support our hypothesis. Demonstration of a direct binding interaction between miRNA and target mRNA will allow for altemative conclusions to be reached, as severa! explanations to the observed trends are possible. This study provides insight into the complexity of epigenetics as it applies to tumorigenesis and sets a platform for reconsideration ofpreviously assumed epigenetic schemes involving EZH2 and miRNAmediated regulation.