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Targeting MYCN-driven transcription by BET-bromodomain inhibition

Item Type:Article
Title:Targeting MYCN-driven transcription by BET-bromodomain inhibition
Creators Name:Henssen, A. and Althoff, K. and Odersky, A. and Beckers, A. and Koche, R. and Speleman, F. and Schäfers, S. and Bell, E. and Nortmeyer, M. and Westermann, F. and De Preter, K. and Florin, A. and Heukamp, L. and Spruessel, A. and Astrahanseff, K. and Lindner, S. and Sadowski, N. and Schramm, A. and Astorgues-Xerri, L. and Riveiro, M.E. and Eggert, A. and Cvitkovic, E. and Schulte, J.H.
Abstract:PURPOSE: Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma. EXPERIMENTAL DESIGN: The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control. RESULTS: OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes. CONCLUSIONS: We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers.
Keywords:3-Ring Heterocyclic Compounds, Acetanilides, Antineoplastic Agents, Cell Line, Gene Expression, Genetic Transcription, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neuroblastoma, Nuclear Proteins, Nude Mice, Transcription Factors, Tumor Cell Line, Animals, Mice
Source:Clinical Cancer Research
Publisher:American Association for Cancer Research
Page Range:2470-2481
Date:May 2016
Official Publication:https://doi.org/10.1158/1078-0432.CCR-15-1449
PubMed:View item in PubMed

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