Cancer promoting transcriptional enhancers controlled by the EMT-activator ZEB1

由 EMT 激活剂 ZEB1 控制的促癌转录增强子

• 批准号: 416775465
• 负责人: Professor Dr. Thomas Brabletz
• 金额: --
• 依托单位: Nikolaus-Fiebiger-Zentrum für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/416775465?language=en
• 关键词: Cancer; promoting; transcriptional; enhancers; controlled

To date, the vast majority of cancer related deaths is caused by the formation of distant metastases. Thus, it is of utmost importance to better understand and predict the metastatic process. During the last two decades we and others could identify cancer cell plasticity, mediated by the embryonic program of Epithelial to Mesenchymal Transition (EMT) and its reverse process (MET), to be a crucial trait driving the metastatic cascade. Our work focuses on the transcription factor ZEB1, a major EMT inducer and known repressor of epithelial genes. We have shown that in aggressive cancers, ZEB1 can turn into a transcriptional activator of tumor-promoting genes. Lately, gene activation via distant transcriptional enhancers emerged as an important metastasis promoting mechanism. Active enhancers are even considered as prognostic and potentially diagnostic tumor markers. Since we have evidence that ZEB1 functions in enhancer activation, we now plan to characterize ZEB1 dependent enhancer regions on a genome wide level. Further, we want to annotate those enhancers to the respective regulated genes and characterize their functions in tumor cell biology. We expect to achieve knowledge about a novel aspect of ZEB1 dependent pro-metastatic functions and to identify novel tumor promoting enhancers that might serve as potential prognostic and diagnostic tools.

迄今为止，绝大多数与癌症相关的死亡是由远处转移的形成引起的。因此，更好地理解和预测转移过程至关重要。在过去的二十年中，我们和其他人可以鉴定出由上皮的胚胎程序到间质转变（EMT）及其反向过程（MET）介导的癌细胞可塑性，这是驱动转移性级联反应的关键特征。我们的工作着重于转录因子ZEB1，这是一种主要的EMT诱导剂和已知的上皮基因阻遏物。我们已经表明，在侵略性癌症中，Zeb1可以变成促肿瘤基因的转录激活因子。最近，通过遥远的转录增强子激活基因作为促进机制的重要转移。活跃的增强剂甚至被认为是预后且潜在的诊断性肿瘤标记物。由于我们有证据表明Zeb1在增强子激活中起作用，因此我们现在计划在基因组广泛水平上表征Zeb1依赖性增强子区域。此外，我们希望将这些增强子注释到各自受调节的基因，并表征它们在肿瘤细胞生物学中的功能。我们期望获得有关Zeb1依赖性促值功能的新颖方面的知识，并确定促进肿瘤的新型肿瘤，从而成为潜在的预后和诊断工具。