文章：

增强剂在癌症中的作用

The role of enhancers in cancer

原文发布日期：2016-07-01

DOI: 10.1038/nrc.2016.62

类型: Review Article

开放获取: 否

要点：

1. Enhancer malfunction is a key process that drives the aberrant regulation of oncogenes in cancer.
2. Enhancer variants contribute more than any other known mechanism to heritable cancer predisposition.
3. Somatic mutations affecting enhancers are common in sporadic tumours. They include copy number alterations that increase the strength of an enhancer, structural rearrangements that direct enhancers to new targets and point mutations or small insertions or deletions (indels) that create new enhancers by altering transcription factor binding sites.
4. Epigenetic mechanisms also commonly alter enhancer activities in cancer.
5. During normal development and homeostasis, very strong enhancers or super-enhancers are found near lineage-specifying genes. During tumorigenesis, super-enhancers commonly form de novo near oncogenes.
6. Strong enhancer activities in cancer cells lock the growth regulatory network to an 'on' state, driving uncontrolled proliferation.
7. Enhancer malfunction can be targeted for cancer therapy. Although transcription is a general property of all cells, cancer cells are more dependent on increased transcription levels from enhancers and, thus, are more sensitive to enhancer inhibition than their normal counterparts.

要点翻译：

1. 增强子功能障碍是驱动癌症中癌基因异常调控的关键过程。
2. 在遗传性癌症易感性中，增强子变异的影响超过任何其他已知机制。
3. 影响增强子的体细胞突变在散发性肿瘤中很常见，包括通过拷贝数变异增强增强子活性、通过结构重排使增强子靶向新基因，以及通过点突变或小片段插入/缺失改变转录因子结合位点从而产生新增强子。
4. 表观遗传机制也常改变癌症中的增强子活性。
5. 在正常发育和稳态过程中，谱系特异性基因附近存在极强的增强子或超级增强子。在肿瘤发生过程中，癌基因附近常会形成全新的超级增强子。
6. 癌细胞中强大的增强子活性将生长调控网络锁定于“开启”状态，驱动不受控的增殖。
7. 增强子功能障碍可作为癌症治疗靶点。虽然转录是所有细胞的普遍功能，但癌细胞更依赖于增强子带来的转录水平提升，因此相比正常细胞对增强子抑制更为敏感。

英文摘要：

Enhancer elements function as the logic gates of the genetic regulatory circuitry. One of their most important functions is the integration of extracellular signals with intracellular cell fate information to generate cell type-specific transcriptional responses. Mutations occurring in cancer often misregulate enhancers that normally control the signal-dependent expression of growth-related genes. This misregulation can result from trans-acting mechanisms, such as activation of the transcription factors or epigenetic regulators that control enhancer activity, or can be caused in cis by direct mutations that alter the activity of the enhancer or its target gene specificity. These processes can generate tumour type-specific super-enhancers and establish a 'locked' gene regulatory state that drives the uncontrolled proliferation of cancer cells. Here, we review the role of enhancers in cancer, and their potential as therapeutic targets.

摘要翻译： 

增强子元件作为基因调控回路的逻辑门，其核心功能之一是将细胞外信号与细胞内命运信息整合，产生细胞类型特异性的转录反应。癌症中发生的突变常导致这些本控信号依赖性生长基因表达的增强子失调。这种失调可能源于反式作用机制，例如激活调控增强子活性的转录因子或表观遗传调控因子；也可能由顺式作用机制引起，即直接突变改变增强子活性或其靶基因特异性。这些过程可产生肿瘤类型特异性的超级增强子，并建立“锁定”的基因调控状态，驱动癌细胞失控增殖。本文综述增强子在癌症中的作用及其作为治疗靶点的潜力。

原文链接：

The role of enhancers in cancer