Unknown,Transcriptomics,Genomics,Proteomics

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Targeting super-enhancer induced gene expression using novel BRD4 inhibitor OTX015 in preclinical models of MYCN-amplified neuroblastoma

ABSTRACT: Bromodomain-containing protein 4 (BRD4) functions as an epigenetic reader and binds to so-called super-enhancer regions of driving oncogenes such as MYC in cancer. We investigated the possibility to target super-enhancer regulated genes in neuroblastoma and in MYCN amplified disease in particular. We used OTX015, the first small-molecule BRD4 inhibitor to enter clinical phase I/II trials in adults, to test the feasibility to specifically target super-enhancer regulated gene-expression in neuroblastoma. BRD4 inhibition lead to significant transcriptional down-regulation of genes that were associated with super-enhancers, supporting the notion that BRD4 preferentially acts at these chromatin sites. BRD4 inhibition not only attenuated MYCN transcription but most significantly affected MYCN-regulated transcriptional programs.

ORGANISM(S): Homo sapiens

SUBMITTER: Anneleen Beckers 

PROVIDER: E-MTAB-3672 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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<h4>Purpose</h4>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.<h4>Experimental design</h4>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  ...[more]

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