Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
Cell Death Dis. 2023 Jan 6;14(1):8. doi: 10.1038/s41419-022-05513-1.
Abnormal activities of distal cis-regulatory elements (CREs) contribute to the initiation and progression of cancer. Gain of super-enhancer (SE), a highly active distal CRE, is essential for the activation of key oncogenes in various cancers. However, the mechanism of action for most tumor-specific SEs still largely remains elusive. Here, we report that a candidate oncogene ETS2 was activated by a distal SE in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The SE physically interacted with the ETS2 promoter and was required for the transcription activation of ETS2. Strikingly, the ETS2-SE activity was dramatically upregulated in both IBD and CRC tissues when compared to normal colon controls and was strongly correlated with the level of ETS2 expression. The tumor-specific activation of ETS2-SE was further validated by increased enhancer RNA transcription from this region in CRC. Intriguingly, a known IBD-risk SNP resides in the ETS2-SE and the genetic variant modulated the level of ETS2 expression through affecting the binding of an oncogenic transcription factor MECOM. Silencing of MECOM induced significant downregulation of ETS2 in CRC cells, and the level of MECOM and ETS2 correlated well with each other in CRC and IBD samples. Functionally, MECOM and ETS2 were both required for maintaining the colony-formation and sphere-formation capacities of CRC cells and MECOM was crucial for promoting migration. Taken together, we uncovered a novel disease-specific SE that distantly drives oncogenic ETS2 expression in IBD and CRC and delineated a mechanistic link between non-coding genetic variation and epigenetic regulation of gene transcription.
远端顺式调控元件 (CREs) 的异常活动导致癌症的发生和发展。超级增强子 (SE) 的获得，一种高度活跃的远端 CRE，是各种癌症中关键癌基因激活所必需的。然而，大多数肿瘤特异性 SE 的作用机制在很大程度上仍然难以捉摸。在这里，我们报告了一个候选癌基因 ETS2 被炎症性肠病 (IBD) 和结直肠癌 (CRC) 中的远端 SE 激活。SE 与 ETS2 启动子物理相互作用，是 ETS2 转录激活所必需的。引人注目的是，与正常结肠对照相比，IBD 和 CRC 组织中 ETS2-SE 的活性显著上调，并且与 ETS2 表达水平强烈相关。该区域增强子 RNA 转录的增加进一步验证了 CRC 中 ETS2-SE 的肿瘤特异性激活。有趣的是，一个已知的 IBD 风险 SNP 位于 ETS2-SE 中，该遗传变异通过影响致癌转录因子 MECOM 的结合来调节 ETS2 的表达水平。MECOM 沉默诱导 CRC 细胞中 ETS2 的显著下调，并且 MECOM 和 ETS2 在 CRC 和 IBD 样本中的水平彼此之间存在很好的相关性。功能上，MECOM 和 ETS2 都需要维持 CRC 细胞的集落形成和球体形成能力，而 MECOM 对于促进迁移至关重要。总之，我们揭示了一种新型疾病特异性 SE，它在 IBD 和 CRC 中远距离驱动致癌 ETS2 表达，并描绘了非编码遗传变异和基因转录的表观遗传调控之间的机制联系。
