Henssen, Anton ORCID: 0000-0003-1534-778X, Althoff, Kristina, Odersky, Andrea, Beckers, Anneleen, Koche, Richard ORCID: 0000-0002-6820-5083, Speleman, Frank, Schaefers, Simon, Bell, Emma, Nortmeyer, Maike, Westermann, Frank, De Preter, Katleen, Florin, Alexandra, Heukamp, Lukas ORCID: 0000-0002-3388-3482, Spruessel, Annika, Astrahanseff, Kathy, Lindner, Sven, Sadowski, Natalie, Schramm, Alexander ORCID: 0000-0001-7670-7529, Astorgues-Xerri, Lucile, Riveiro, Maria E., Eggert, Angelika, Cvitkovic, Esteban and Schulte, Johannes H. (2016). Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition. Clin. Cancer Res., 22 (10). S. 2470 - 2482. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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. (C) 2015 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Henssen, AntonUNSPECIFIEDorcid.org/0000-0003-1534-778XUNSPECIFIED
Althoff, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odersky, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckers, AnneleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koche, RichardUNSPECIFIEDorcid.org/0000-0002-6820-5083UNSPECIFIED
Speleman, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefers, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bell, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nortmeyer, MaikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Preter, KatleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, LukasUNSPECIFIEDorcid.org/0000-0002-3388-3482UNSPECIFIED
Spruessel, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Astrahanseff, KathyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sadowski, NatalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schramm, AlexanderUNSPECIFIEDorcid.org/0000-0001-7670-7529UNSPECIFIED
Astorgues-Xerri, LucileUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riveiro, Maria E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cvitkovic, EstebanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-275670
DOI: 10.1158/1078-0432.CCR-15-1449
Journal or Publication Title: Clin. Cancer Res.
Volume: 22
Number: 10
Page Range: S. 2470 - 2482
Date: 2016
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
C-MYC; SELECTIVE-INHIBITION; SUPER-ENHANCERS; NEUROBLASTOMA; PROGRESSION; EXPRESSION; CANCER; GENES; TUMOR; BRD4Multiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27567

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