Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China.
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Nucleic Acids Res. 2019 Feb 20;47(3):1255-1267. doi: 10.1093/nar/gky1207.
As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer-associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.
作为儿童和青少年中第二常见的恶性骨肿瘤，尤文肉瘤是由嵌合性癌蛋白引发和加剧的，最常见的是 EWS-FLI1。在这项研究中，我们应用表观基因组分析来描述这种癌症中的转录失调，重点研究超级增强子及其相关的转录调控机制。我们证明，超级增强子相关的转录本在 EWS-FLI1 靶基因中显著富集，有助于疾病的异常转录网络，并介导尤文肉瘤对转录抑制的特殊敏感性。通过综合分析，我们确定 MEIS1 是一个超级增强子驱动的癌基因，它与 EWS-FLI1 一起在转录调控中发挥作用，并在尤文肉瘤中发挥关键的生存促进作用。此外，另一个超级增强子相关基因 APCDD1，作为 MEIS1 和 EWS-FLI1 的下游靶点，也被确定为这种恶性肿瘤中的一个新的促肿瘤因子。这些数据描绘了尤文肉瘤中超级增强子介导的转录失调，并揭示了许多候选癌基因，可用于进一步了解该疾病的分子发病机制。
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