Cancer promoting transcriptional enhancers controlled by the EMT-activator ZEB1

迄今为止，绝大多数癌症相关死亡是由远处转移的形成引起的。因此，更好地了解和预测转移过程至关重要。在过去的二十年里，我们和其他人可以确定癌细胞的可塑性，由上皮细胞向间质细胞转化（EMT）及其逆转过程（MET）的胚胎程序介导，是驱动转移级联的关键特征。我们的工作集中在转录因子ZEB1，一个主要的EMT诱导剂和已知的上皮基因的阻遏物。我们已经证明，在侵袭性癌症中，ZEB1可以变成促肿瘤基因的转录激活因子。最近，通过远端转录增强子的基因激活成为重要的转移促进机制。活性增强子甚至被认为是预后和潜在的诊断肿瘤标志物。由于我们有证据表明ZEB1在增强子激活中起作用，我们现在计划在全基因组水平上表征ZEB1依赖的增强子区域。此外，我们希望注释这些增强子各自的调节基因，并表征其在肿瘤细胞生物学中的功能。我们期望获得有关ZEB1依赖性促转移功能的新方面的知识，并确定可能作为潜在预后和诊断工具的新型肿瘤促进增强剂。

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.