期刊
EPIGENETICS
卷 10, 期 6, 页码 460-466出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15592294.2015.1034416
关键词
super-enhancer; BET inhibitor; H3K27Ac; JQ1; BRD4; Merkel cell carcinoma; BET, bromodomain and extra-terminal domain family; BRD, bromodomain; qRT-PCR, quantitative reverse transcription PCR; ChIP, Chromatin immunoprecipitation; qPCR, quantitative PCR; MCC, Merkel cell carcinoma
资金
- Translational Research Institute (TRI) through the NIH National Center for Research Resources [UL1TR000039, KL2TR000063]
- National Center for Advancing Translational Sciences
- Department of Dermatology, the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences
- Arkansas Biosciences Institute
- Arkansas Tobacco Settlement Proceeds Act
- [R01GM106024]
- [R33CA173264]
- [P30GM103450]
- [P20GM103429]
Pathologic c-Myc expression is frequently detected in human cancers, including Merkel cell carcinoma (MCC), an aggressive skin cancer with no cure for metastatic disease. Bromodomain protein 4 (BRD4) regulates gene transcription by binding to acetylated histone H3 lysine 27 (H3K27Ac) on the chromatin. Super-enhancers of transcription are identified by enrichment of H3K27Ac. BET inhibitor JQ1 disrupts BRD4 association with super-enhancers, downregulates proto-oncogenes, such as c-Myc, and displays antitumor activity in preclinical animal models of human cancers. Here we show that an enhancer proximal to the c-Myc promoter is enriched in H3K27Ac and associated with high occupancy of BRD4, and coincides with a putative c-Myc super-enhancer in MCC cells. This observation is mirrored in tumors from MCC patients. Importantly, depleted BRD4 occupancy at the putative c-Myc super-enhancer region by JQ1 correlates with decreased c-Myc expression. Thus, our study provides initial evidence that super-enhancers regulate c-Myc expression in MCC.
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