The dual role of C/EBPδ in cancer
Leonie Hartl, JanWillem Duitman, Maarten F. Bijlsma, C. Arnold Spek
Abstract
CCAAT/Enhancer-Binding Protein delta (C/EBPδ) is a transcription factor involved in differentiation and inflammation. While sparsely expressed in adult tissues, aberrant expression of C/EBPδ has been associated with different cancers. Initially, re-expression of C/EBPδ in cell cultures limited tumor cell proliferation, assigning it a tumor suppressor role. However, opposing observations were made in pre-clinical models and patients, suggesting that C/EBPδ not only mediates cell proliferation but dictates a broader spectrum of tumorigenesis-related effects. It is now widely accepted that C/EBPδ contributes to an inflammatory, tumor-promoting microenvironment, aids hypoxia adaption and contributes to the recruitment of blood vessels for improved nutrient supply to tumor cells and facilitated extravasation. This review summarizes the work published on this transcription factor in the field of cancer over the past decade. It points out areas in which a consensus on C/EBPδ’s role appears to emerge and seek to explain seemingly contradictory results. • C/EBPδ can induce tumor-limiting differentiation and halt cell cycle progression. • But C/EBPδ also forms a positive feedback-loop with HIF-1α to aid hypoxia adaption. • C/EBPδ promotes drug resistance in tumor and stromal cells via diverse mechanisms. • The stromal compartment is further remodeled by C/EBPδ to facilitate tumorigenesis. • C/EBPδ’s anti-tumor effects are often overruled by its tumor-promoting activities.