BET bromodomain inhibitors suppress EWS-FLI1-dependent transcription and the IGF1 autocrine mechanism in Ewing sarcoma
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Sudan N. Loganathan1,2, Nan Tang3, Jonathan T. Fleming4, Yufang Ma5, Yan Guo6, Scott C. Borinstein7, Chin Chiang4, Jialiang Wang1,2,5,6
1Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, USA
2Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
3Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
4Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
5Department of Neurological Surgery, Vanderbilt University, Nashville, TN, USA
6Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA
7Department of Pediatrics, Vanderbilt University, Nashville, TN, USA
Jialiang Wang, email: firstname.lastname@example.org
Keywords: BET bromodomain protein, Ewing sarcoma, EWS-FLI1, IGF1, BRD4
Received: February 19, 2016 Accepted: May 20, 2016 Published: June 01, 2016
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.
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