PDF(Pubmed)
Abstract：
In addition to genetic variants and copy number alterations, epigenetic deregulation of oncogenes and tumor suppressors is a major contributor in cancer development and propagation. Regulatory elements for gene transcription regulation can be found in promoters which are located in the vicinity of transcription start sites but also at a distance, in enhancer sites, brought to interact with proximal sites when occupied by enhancer protein complexes. These sites provide most of the specific regulatory sequences recognized by transcription factors. A sub-set of enhancers characterized by a longer structure and stronger activity, called super-enhancers, are critical for the expression of specific genes, usually associated with individual cell type identity and function. Super-enhancers show deregulation in cancer, which may have profound repercussions for cancer cell survival and response to therapy. Dysfunction of super-enhancers may result from multiple mechanisms that include changes in their sequence, alterations in the topological neighborhoods where they belong, and alterations in the proteins that mediate their function, such as transcription factors and epigenetic modifiers. These can become potential targets for therapeutic interventions. Genes that are targets of super-enhancers are cell and cancer type specific and could also be of interest for therapeutic targeting. In colorectal cancer, a super-enhancer regulated and over-expressed oncogene is MYC, under the influence of the WNT/β-catenin pathway. Identification and targeting of additional oncogenes regulated by super-enhancers in colorectal cancer may pave the way for combination therapies targeting the super-enhancer machinery and signal transduction pathways that regulate the specific transcription factors operative on them.
摘要：
除了遗传变异和拷贝数改变，癌基因和肿瘤抑制基因的表观遗传失调是癌症发展和传播的主要因素。基因转录调控的调控元件可以在位于转录起始位点附近但也有一定距离的启动子中找到。在增强子位点，被增强子蛋白复合物占据时与近端位点相互作用。这些位点提供了转录因子识别的大多数特异性调节序列。以更长的结构和更强的活性为特征的增强子子集，叫做超级增强剂，对特定基因的表达至关重要，通常与单个细胞类型的身份和功能有关。超级增强子在癌症中表现出失调，这可能对癌细胞的存活和对治疗的反应产生深远的影响。超级增强子的功能障碍可能是由多种机制引起的，包括序列的变化，它们所属的拓扑邻域的变化，以及介导其功能的蛋白质的改变，如转录因子和表观遗传修饰因子。这些可以成为治疗干预的潜在目标。作为超增强子的靶标的基因是细胞和癌症类型特异性的,并且对于治疗靶向也可能是感兴趣的。在结直肠癌中，超增强子调节和过表达的癌基因是MYC，在WNT/β-catenin通路的影响下。在结直肠癌中由超增强子调节的其他癌基因的鉴定和靶向可以为靶向调节对其起作用的特定转录因子的超增强子机制和信号转导途径的组合疗法铺平道路。
