Abstract C23: Epigenetic regulation of miRNAs and influence on malignancy in Ewing tumors

Although microRNAs (miRNA) were shown to be involved in cancer progression of many tumor entities, little is known about the role of non-coding RNAs in Ewing Tumor (ET) pathogenesis. The highly malignant ET comprise the second most common type of bone associated cancers in children and are characterized by oncogenic ews/ets translocations. We previously observed the histone methyltransferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be regulated by EWS-FLI1 and highly increased in ET. Here we demonstrate that EZH2 occupies promotor regions of putative tumor suppressor miRNAs and differentiation associated miRNAs in ET. We show that EZH2 mediates silencincig of miRNA expression via histone modification as well as DNA methylation and that these miRNAs are reactivated upon EZH2 knock down or treatment with inhibitors histone deacetylation and DNA methylation. In addition, we show that the well-known oncogenic miRNA221 is highly expressed in ET and processed in the presence of Argonaute (AGO) protein 2. Using RNA interference we observed that AGO1 and AGO2 mediated processes affect cellular invasiveness and anchorage-independent proliferation in vitro and influence ET growth and metastasis in immunodeficient Rag2−/−γC−/− mice, confirming an involvement of non-coding RNAs in ET pathogenesis. Taken together, these data illuminate the hitherto unknown epigenetic regulation of miRNA expression by EZH2 in ET and a general involvement of noncoding RNA in ET-pathogenesis, opening the avenue for new therapeutic modalities i.e. the implementation of miRNA therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C23.