Abstract IA13: Mechanisms of chromatin regulation by the EWS-FLI1 fusion protein in Ewing sarcoma

Abstract

Abstract Our laboratory uses genomic approaches to identify and characterize abnormalities in gene regulation in cancer. Large scale sequencing studies have shown that transcriptional regulators, including transcription factors, chromatin modifiers and histones, are frequently altered in cancer and may thus contribute to transformation through widespread changes in gene expression programs. This is particularly evident in pediatric tumors, which have low numbers of recurrent genetic events and where alterations in a transcriptional regulator may be the sole genetic “driver”. In the case of Ewing sarcoma, the second most common pediatric bone cancer, translocations involving EWS and the ETS transcription factor FLI1 generate a fusion protein that has been shown to be essential for the growth and survival of tumor cells. We recently used genome-wide chromatin profiling to study the mechanisms of action of EWS-FLI1 and found that it utilizes two distinct patterns of chromatin remodeling to either activate or repress enhancers. At repeats of the GGAA ETS recognition motif, which are poorly conserved in evolution, EWS-FLI1 multimers induce chromatin opening and create active enhancers de novo. These repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. In contrast, at conserved enhancers containing canonical ETS motifs, EWS-FLI1 displaces wild-type ETS transcription factors and leads to significant reductions in enhancer activity. These different chromatin remodeling mechanisms are associated with the repression of tumor suppressors and mesenchymal lineage genes and the activation of oncogenes and potential therapeutic targets. Our studies thus illustrate how chromatin profiling can reveal mechanisms of chromatin regulation that are critical in establishing an oncogenic regulatory program in cancer. Citation Format: Miguel N. Rivera. Mechanisms of chromatin regulation by the EWS-FLI1 fusion protein in Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA13.