Characterization of the mechanisms of transcriptional regulation by EWS/FLI in ewing sarcoma

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Title Characterization of the mechanisms of transcriptional regulation by EWS/FLI in ewing sarcoma
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Sankar, Savita
Date 2013-08
Description Ewing sarcoma is a highly aggressive pediatric malignancy that is characterized by a chromosomal translocation-derived fusion protein, Ewing sarcoma (EWS)/ Friend leukemia insertion (FLI), EWS/FLI. EWS/FLI is an aberrant transcription factor and its downstream targets contribute to oncogenic transformation in Ewing sarcoma. However, the mechanisms of transcriptional regulation by EWS/FLI and the full complement of direct targets of EWS/FLI were previously unknown. The work documented in this dissertation describes a novel basis for EWS/FLI function in gene activation, and also uncovers a mechanism by which EWS/FLI directly represses a subset of critical targets genes in Ewing sarcoma. Through the identification of direct in vivo targets of EWS/FLI, we made an unexpected discovery that EWS/FLI activates some of its critical target genes, including NR0B1 and GSTM4, by binding to microsatellite repeats. These findings suggest a new paradigm for cancer-relevant gene regulation by EWS/FLI, and perhaps other ETS family members. In addition to the microsatellite repeats, EWS/FLI regulates some of its target genes through the canonical high-affinity consensus E-26 oncogene (ETS) site. We focused on one such target gene, GLI1, and uncovered a novel role for GLI1 and its downstream target, KRT17, in coordinating two cancer-relevant functions: oncogenic transformation and cellular adhesion in Ewing sarcoma. iv The functional relationship between wild-type EWS and the EWS/FLI fusion protein in Ewing sarcoma was largely unknown. Through global transcription profiling and mechanistic studies we demonstrated that EWS and EWS/FLI coregulate a subset of genes in Ewing sarcoma and that EWS functions as a cofactor of the REST transcription factor to repress neuronal differentiation genes. These data suggest that EWS, and consequently EWS/FLI, have transcriptional repressive roles in Ewing sarcoma. We next focused on identifying and characterizing the mechanism underlying EWS/FLI-mediated direct transcriptional repression. We demonstrated that EWS/FLI interacts with the nucleosome remodeling and histone deacetylase (NuRD) corepressor complex to repress critical tumor suppressor genes in Ewing sarcoma. These data identify inhibitors of the NuRD complex components as potentially effective therapeutic agents for the treatment of Ewing sarcoma. Taken together, the work presented in this dissertation advances our molecular understanding of EWS/FLI-mediated gene regulation in Ewing sarcoma.
Type Text
Publisher University of Utah
Subject MESH Sarcoma, Ewing; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Transcription Factors; Transcriptional Activation; Oncogenes; Mesenchymal Stromal Cells; Repressor Proteins; Histone Deacetylases; Carcinogenesis; Translocation, Genetic; Microsatellite Repeats
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Characterization of the Mechanisms of Transcriptional Regulation by EWS/FLI in Ewing Sarcoma. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management Copyright © Savita Sankar 2013
Format application/pdf
Format Medium application/pdf
Format Extent 40,812,279 bytes
Source Original in Marriott Library specials Collections.
ARK ark:/87278/s6hh9t88
Setname ir_etd
ID 196611
Reference URL https://collections.lib.utah.edu/ark:/87278/s6hh9t88
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