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 <i>c-Myc</i>, and displays antitumor activity in preclinical animal models of human cancers. Here we show that an enhancer proximal to the <i>c-Myc</i> promoter is enriched in H3K27Ac and associated with high occupancy of BRD4, and coincides with a putative <i>c-Myc</i> super-enhancer in MCC cells. This observation is mirrored in tumors from MCC patients. Importantly, depleted BRD4 occupancy at the putative <i>c-Myc</i> 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.

病理性c-Myc（c-Myc）表达在人类多种癌症中频繁检出，其中包括默克尔细胞癌（Merkel cell carcinoma, MCC）——一种转移性疾病尚无治愈手段的侵袭性皮肤癌。溴结构域蛋白4（Bromodomain protein 4, BRD4）可通过结合染色质上的乙酰化组蛋白H3赖氨酸27（acetylated histone H3 lysine 27, H3K27Ac）调控基因转录。转录超级增强子可通过H3K27Ac富集进行鉴定。BET抑制剂JQ1可破坏BRD4与超级增强子的结合，下调包括c-Myc在内的原癌基因，并在人类癌症的临床前动物模型中展现出抗肿瘤活性。本研究发现，c-Myc启动子近端的增强子存在H3K27Ac富集现象，且伴随BRD4高占据，与默克尔细胞癌细胞中推定的c-Myc超级增强子区域重合。这一观察结果在默克尔细胞癌患者的肿瘤组织中同样得到验证。值得注意的是，JQ1介导的推定c-Myc超级增强子区域BRD4占据量降低，与c-Myc表达水平下降相关。综上，本研究首次提供证据表明，超级增强子可调控默克尔细胞癌中的c-Myc表达。