CCAAT/enhancer binding protein delta (C/EBPδ) demonstrates a dichotomous role in tumour initiation and promotion of epithelial carcinoma

Abstract

Background: CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basicleucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBPδ in different tumours, such as glioblastoma and breast cancer either promotes tumour progression or inhibits growth and has low expression in normal tissue until activated by cytotoxic stressors. Methods: Higher overall expression of C/EBPδ in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBPδ in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBPδ in proliferation, migration, and the epithelial to mesenchymal transition. Findings: Expression of C/EBPδ induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBPδ in epithelial cancer cell lines did not have significant effects on proliferation, yet overexpression demonstrated downregulation of growth, similar to normal fallopian tube cells. C/EBPδ promoted a partial mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating Vimentin and N-cadherin in FTE cells and increased migratory activity, which suggests a regulatory role in the epithelial-mesenchymal plasticity of these cells. Interpretation: Our findings suggest that C/EBPδ regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis.

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

“…As C/EBPδ induces growth arrest [16,17], it is tempting to speculate that the loss of C/EBPδ conversely facilitates tumorigenesis. Such a role of C/EBPδ would be in line with previous studies showing that C/EBPδ is a tumor suppressor in leukemia, breast cancer, hepatocellular carcinoma and cervical cancer [21][22][23][24][25][26][27][28].…”

“…Moreover, C/EBPδ is involved in the regulation of pro-apoptotic gene expression and growth arrest during mammary gland involution [ 19 , 20 ]. In line with these data, C/EBPδ indeed acts as a tumor suppressor in breast cancer [ 21 , 22 , 23 ], ovarian serous carcinoma [ 24 ], cervical carcinoma [ 25 ], leukemia [ 26 ] and hepatocellular carcinoma [ 27 , 28 ].…”

“…C/EBPδ has been found to negatively affect tumor growth by inducing growth arrest and differentiation [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Recently, however, C/EBPδ was also suggested to drive tumor progression and/or metastasis in certain tumor types [ 29 , 30 , 31 , 32 ], suggesting that C/EBPδ may either suppress or promote tumor progression in a context specific manner.…”

SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD

“…CEBPD is a vital transcriptional regulator in ovarian cancer. It promotes cell migration, EMT/MET, and cell survival by the IL‐6/STAT3 signaling pathway, while maintaining genome stability 53 . In gliomas, DN‐ATF5 acts as a tumor suppressor by blocking the transcriptional activity of CEBPD 54 .…”

Papel de CEBPD en el desarrollo de resistencias del cáncer de próstata al tratamiento hormonal y su posible regulación por AR-V7

“…En este sentido, a principios de año, se publicó un trabajo en el que se describe un papel dual de CEBPD regulando la proliferación y migración de forma contraria. En concreto, en este estudio, demuestran que la sobreexpresión de CEBPD en líneas celulares de cáncer epitelial humano produce una parada en el ciclo celular y aumenta la migración [20]. Por otro lado, en otro trabajo en el que silenciaron este gen en células epiteliales mamarias y en fibroblastos de embrión de ratón demostraron que la disminución de CEBPD promovía la migración, lo que coincide con nuestros resultados [21].…”