Cancer and Metastasis Reviews ( IF 7.7 ) Pub Date : 2023-04-14 , DOI: 10.1007/s10555-023-10103-4
Megan Bacabac 1, 2 , Wei Xu 1, 2
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Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regulatory elements and trans-acting factors. Large clusters of enhancers known as “super-enhancers” drive robust expression of cell-fate determining transcription factors in cell identity. Cancer cells can take advantage of super-enhancers and become transcriptionally addicted to them leading to tumorigenesis and metastasis. Additionally, the cis-regulatory landscape of cancer includes aberrant super-enhancers that are not present in normal cells. The landscape of super-enhancers in cancer is characterized by high levels of histone H3K27 acetylation and bromodomain-containing protein 4 (BRD4), and Mediator complex. These chromatin features facilitate the identification of cancer type-specific and cell-type-specific super-enhancers that control the expression of important oncogenes to stimulate their growth. Disruption of super-enhancers via inhibiting BRD4 or other epigenetic proteins is a potential therapeutic option. Here, we will describe the discovery of super-enhancers and their unique characteristics compared to typical enhancers. Then, we will highlight how super-enhancer-associated genes contribute to cancer progression in different solid tumor types. Lastly, we will cover therapeutic targets and their epigenetic modulators.
中文翻译:
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癌症中的致癌超级增强剂:机制和治疗靶点
激活癌基因以维持增殖信号并启动转移是癌症的重要标志。癌基因在癌细胞中扩增或过度表达,并且过度表达通常在转录水平上受到控制。基因表达受到许多顺式调控元件和反式作用因子的严格控制。被称为“超级增强子”的大簇增强子可驱动细胞身份中决定细胞命运的转录因子的稳健表达。癌细胞可以利用超级增强子并对其进行转录上瘾,从而导致肿瘤发生和转移。此外,癌症的顺式调控景观包括正常细胞中不存在的异常超级增强子。癌症中超级增强子的特征是高水平的组蛋白 H3K27 乙酰化和含溴结构域蛋白 4 (BRD4) 以及介体复合物。这些染色质特征有助于识别癌症类型特异性和细胞类型特异性超级增强子,这些超级增强子控制重要癌基因的表达以刺激其生长。通过抑制 BRD4 或其他表观遗传蛋白来破坏超级增强子是一种潜在的治疗选择。在这里,我们将描述超级增强子的发现及其与典型增强子相比的独特特征。然后,我们将重点介绍超级增强子相关基因如何促进不同实体瘤类型的癌症进展。最后,我们将介绍治疗靶点及其表观遗传调节剂。