Abstract PR04: Genomic and epigenomic interactions of an Ewing sarcoma-specific long noncoding RNA

Abstract

Abstract Ewing sarcoma is a highly invasive pediatric bone malignancy with a 30% 5-year survival rate for patients with metastatic disease. The EWS-FLI1 fusion gene is detected in 90% of these cases, and functions as a transcription factor that regulates oncogenesis-related gene expression. The functions of EWS-FLI1 and other oncogenes have been explored in the past to detect potential therapeutic targets. Here we report the functions and interactions of a long intergenic non-coding RNA (lincRNA) that is unique to Ewing sarcoma. Gene expression profiling studies identified a significant association of lincRNA, AK057037, with Ewing sarcoma. Chromatin immunoprecipitation (ChIP) and functional studies with EWS-FLI1 detected direct regulation of this multi-exonic, multivariant lincRNA by EWS-FLI1. Comparative RNA-seq analysis on primary and metastatic tumor cell lines showed increased transcriptional activity in the metastatic cell line. In vitro and in vivo functional studies with the lincRNA confirmed its role as an oncogene in promoting anchorage independence and metastasis of the Ewing sarcoma cell lines and xenograft models, respectively. Further, ChIP studies showed that AK057037 was bound to Ezh2, a methyltransferase in the polycomb repressor complex 2 (PRC2). ChIP-seq using histone antibodies showed changes in methylation pattern in promoter regions of genes affected by the lincRNA knockdown. In conclusion, the lincRNA AK057037 behaves as an oncogene in Ewing sarcoma. Its association with the PRC2 complex allows for chromatin remodeling such that it promotes metastasis by perturbing transcription of genes involved in migration in this malignancy. This abstract is also presented as Poster A33. Citation Format: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, William A. May, Philipp Kapranov, Robert A. Arceci, Timothy J. Triche. Genomic and epigenomic interactions of an Ewing sarcoma-specific long noncoding RNA. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR04.