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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma
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Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

机译：默克尔细胞癌中富含H3K27Ac的增强子区域BRD4的破坏与c-Myc表达降低有关

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摘要

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.
机译：在人类癌症中经常检测到病理性c-Myc表达，包括默克尔细胞癌（MCC），这是一种无法治愈转移性疾病的侵袭性皮肤癌。 Bromodomain蛋白4（BRD4）通过与染色质上的乙酰化组蛋白H3赖氨酸27（H3K27Ac）结合来调节基因转录。通过富集H3K27Ac来鉴定转录的超级增强子。 BET抑制剂JQ1破坏了BRD4与超级增强子的结合，下调了原癌基因，例如c-Myc，并在人类癌症的临床前动物模型中显示出抗肿瘤活性。在这里，我们显示了接近c-Myc启动子的增强子富含H3K27Ac，并与BRD4的高占用率相关，并且与MCC细胞中推定的c-Myc超增强剂相吻合。该观察结果反映在来自MCC患者的肿瘤中。重要的是，JQ1在假定的c-Myc超级增强子区域消耗的BRD4占用与c-Myc表达降低有关。因此，我们的研究提供了超级增强剂调节MCC中c-Myc表达的初步证据。

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