Abstract
Ewing sarcoma is driven by characteristic chromosomal translocations between the EWSR1 gene with genes encoding ETS family transcription factors (EWS-ETS), most commonly FLI1. However, direct pharmacological inhibition of transcription factors like EWS-FLI1 remains largely unsuccessful. Active gene transcription requires orchestrated actions of many epigenetic regulators, such as the bromodomain and extra-terminal domain (BET) family proteins. Emerging BET bromodomain inhibitors have exhibited promising antineoplastic activities via suppression of oncogenic transcription factors in various cancers. We reasoned that EWS-FLI1-mediated transcription activation might be susceptible to BET inhibition. In this study, we demonstrated that small molecule BET bromodomain inhibitors repressed EWS-FLI1-driven gene signatures and downregulated important target genes. However, expression of EWS-FLI1 was not significantly affected. Repression of autocrine IGF1 by BET inhibitors led to significant inhibition of the IGF1R/AKT pathway critical to Ewing sarcoma cell proliferation and survival. Consistently, BET inhibitors impaired viability and clonogenic survival of Ewing sarcoma cell lines and blocked EWS-FLI1-induced transformation of mouse NIH3T3 fibroblast cells. Selective depletion of individual BET genes partially phenocopied the actions of BET inhibitors. Finally, the prototypical BET inhibitor, JQ1, significantly repressed Ewing sarcoma xenograft tumor growth. These findings suggest therapeutic potential of BET inhibitors in Ewing sarcoma and highlight an emerging paradigm of using epigenetic agents to treat cancers driven by fusion transcription factors.
Highlights
Ewing sarcoma is a group of highly malignant bone and soft tissue tumors that most often occur in children, teenagers, and young adults
We first examined the impact of bromodomain and extra-terminal domain (BET) inhibition on expression profiles of Ewing sarcoma cells by RNA-seq
We found that a substantial percentage (~22%) of genes downregulated > 2 folds upon JQ1 treatment were repressed by knockdown of EWS-FLI1
Summary
Ewing sarcoma is a group of highly malignant bone and soft tissue tumors that most often occur in children, teenagers, and young adults. It is defined by unique chromosomal translocations that give rise to fusion proteins comprising a RNA binding protein EWS (encoded by EWSR1) and one of the ETS family transcription factors [1]. Inclusion of the constitutively active promoter of the EWSR1 gene leads to high levels of www.impactjournals.com/oncotarget expression [2] As such, these chimeric transcription factors result in extensive transcriptional reprogramming in Ewing sarcoma cells [3]. No EWS-ETS target genes have been identified as effective stand-alone therapeutic targets
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