Die funktionelle Interaktion von NFATc1 und EZH2 in der Karzinogenese des Pankreas

To this day, pancreatic cancer is considered one of the most aggressive solid tumors of all. This is due to aggressive growth behaviour, early invasion and metastasis, and pronounced resistance to therapy. It is therefore essential to develop new therapeutic strategies that can control growth behaviour and overcome resistance to conventional chemotherapy. In preliminary work by the Ellenrieder group, the transcription factor "nuclear factor of activated T-cells" (briefly: NFATc1) was identified as a relevant oncogene in the development and progression of pancreatic ductal carcinoma. In this thesis, its interaction with histone methyltransferase EZH2, which belongs to the catalytic subunit of the PRC2-complex and whose role in carcinogenesis and tumor progression is strongly context-dependent, was investigated. In mRNA-seq analyses, we were able to identify EZH2 as one of the most significantly differentially expressed NFATc1 target genes. We found that NFATc1 induces gene expression of EZH2 by binding directly to its promoter. Furthermore, it could be shown in this work that EZH2 and NFATc1 form protein complexes and that this protein is regulated by posttranslational phosphorylation of EZH2 to serine-21. Based on accompanying investigations by our research group and results from other research groups, we postulate that the phosphorylation of EZH2 to serine-21 occurs by signal-regulated kinases such as the oncogenic kinase GSK3β. Consistent with these results, it could be demonstrated that pharmacological blockade of GSK3β-mediated phosphorylation of EZH2 leads to a disruption of the formation of the NFATc1/EZH2-complex. After further functional characterization of its role in pancreatic cancer progression, the identified complex could represent a promising target structure for new therapeutic approaches in the treatment of pancreatic cancer.