Chin Chiang
Professor of Cell and Developmental Biol
Last active: 3/30/2020

BET bromodomain inhibitors suppress EWS-FLI1-dependent transcription and the IGF1 autocrine mechanism in Ewing sarcoma.

Loganathan SN, Tang N, Fleming JT, Ma Y, Guo Y, Borinstein SC, Chiang C, Wang J
Oncotarget. 2016 7 (28): 43504-43517

PMID: 27259270 · PMCID: PMC5190040 · DOI:10.18632/oncotarget.9762

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.

MeSH Terms (29)

Animals Antineoplastic Agents Autocrine Communication Azepines Bone Neoplasms Cell Line, Tumor Cell Proliferation Cell Survival Epigenesis, Genetic Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Insulin-Like Growth Factor I Mice Mice, Nude NIH 3T3 Cells Oncogene Proteins, Fusion Proteins Proto-Oncogene Protein c-fli-1 Proto-Oncogene Proteins c-akt Receptor, IGF Type 1 Receptors, Somatomedin RNA-Binding Protein EWS Sarcoma, Ewing Signal Transduction Transcription, Genetic Triazoles Xenograft Model Antitumor Assays

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