(PQB-2) "Driver" vs. "passenger" epigenetic events in Ewing sarcoma

Research Inst Nationwide Children'S Hosp, Columbus OH

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Ewing sarcoma is a highly malignant bone-associated cancer of children and young adults that harbors the EWS/FLI fusion protein. EWS/FLI is the key driver mutation in Ewing sarcoma because it is expressed in nearly all cases of the disease, it functions as an oncoprotein in model systems, and inhibition of EWS/FLI expression or function in Ewing sarcoma cell lines causes a loss of the oncogenic phenotype. EWS/FLI functions as an aberrant transcription factor to both activate and repress critical target genes that modulate the cancerous phenotype. Because of its absolute reliance on a single mutant transcription factor, Ewing sarcoma provides an unparalleled model to understand the relationship between a driver mutation and driver versus passenger epigenetic events in oncogenic transformation. Our published data demonstrate that EWS/FLI functions both as a transcriptional activator, and as a transcriptional repressor, at important target genes. We found that EWS/FLI functions via interaction with the nucleosome remodeling and deacetylase (NuRD) co- repressor complex to mediate transcriptional repression, and that NuRD-associated histone deacetylase (HDAC) and lysine-specific demethylase 1 (LSD1) activities are required for this function. In contrast, the mechanisms by which EWS/FLI mediates transcriptional activation are less well understood, but our preliminary data indicate that LSD1 function is also required for this activity. We therefore hypothesize that LSD1 serves as a key epigenetic regulator in Ewing sarcoma, and that its specific genomic localization is specified via its interaction with EWS/FLI to direct driver epigenetic changes at target genes critical for the Ewing sarcoma cancerous phenotype.