Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma.
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.
a Department of Biochemistry and Molecular Biology; University of Arkansas for Medical Sciences ; Little Rock , AR , USA.
Deepanwita
D
Sengupta
Aarthi
A
Kannan
Malan
M
Kern
Mauricio A
MA
Moreno
Emre
E
Vural
Brendan
B
Stack
James Y
JY
Suen
Alan J
AJ
Tackett
Ling
L
Gao
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis* / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D056484:Jumonji Domain-Containing Histone Demethylases; D009687:Nuclear Proteins; D020598:Proto-Oncogene Proteins c-myb; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C524220:KDM6B protein, human
BET inhibitor; BET, bromodomain and extra-terminal domain family; BRD, bromodomain; BRD4; ChIP, Chromatin immunoprecipitation; H3K27Ac; JQ1; MCC, Merkel cell carcinoma; Merkel cell carcinoma; qPCR, quantitative PCR; qRT-PCR, quantitative reverse transcription PCR; super-enhancer