CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

SIMPLE SUMMARY: Here we show that a protein called C/EBPδ is present in healthy pancreas tissue but almost absent in pancreas tumors. Patients with less C/EBPδ in their tumors had the most metastases and the worst survival chances, showing that C/EBPδ has tumor-suppressive properties in pancreatic cancer. In this study, we reactivated C/EBPδ in pancreatic cancer cells in vitro and observed a reduction in cell proliferation in a 2-dimentional and 3-dimensional space. This implies that tumor cells grow slower when C/EBPδ is activated and they are likely also less capable to escape the primary tumor in order to form metastases. Conversely, when we deleted C/EBPδ in pancreatic cancer cells, we observed accelerated growth. We suggest that reactivating C/EBPδ can suppress tumor growth and formation of metastases, thereby improving patient survival. ABSTRACT: CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBPδ in these contexts. Here, we explore the role of C/EBPδ in pancreatic cancer. We determined C/EBPδ expression in biopsies from pancreatic cancer patients using public gene-expression datasets and in-house tissue microarrays. We found that C/EBPδ is highly expressed in healthy pancreatic ductal cells but lost in pancreatic ductal adenocarcinoma. Furthermore, loss of C/EBPδ correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients. In accordance with this, in vitro experiments showed reduced clonogenic capacity and proliferation of pancreatic ductal adenocarcinoma cells following C/EBPδ re-expression, concurrent with decreased sphere formation capacity in soft agar assays. We thus report a previously unrecognized but important tumor suppressor role of C/EBPδ in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer. Moreover, our findings suggest that restoration of C/EBPδ activity could hold therapeutic value in pancreatic ductal adenocarcinoma, although the latter claim needs to be substantiated in future studies.