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

ABSTRACT: BACKGROUND:CCAAT/enhancer binding protein delta (C/EBP?,CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBP? 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/EBP? in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBP? in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBP? in proliferation, migration, and the epithelial to mesenchymal transition. FINDINGS:Expression of C/EBP? induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBP? 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/EBP? 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/EBP? regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis. FUND: This study was funded by the CDMRP Ovarian Cancer program (W81WH-0701-0371, W81XWH-18-1-0072), the Princess Margaret Cancer Centre Foundation, Foundation for Women's Cancer - The Belinda-Sue/Mary-Jane Walker Fund, Colleen's Dream Foundation and Sylvester Comprehensive Cancer Center.

SUBMITTER: Sowamber R

PROVIDER: S-EPMC6603855 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Sowamber Ramlogan R Chehade Rania R Bitar Mahmoud M Dodds Leah V LV Milea Anca A Slomovitz Brian B Shaw Patricia A PA George Sophia H L SHL

EBioMedicine 20190509

<h4>Background</h4>CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basic-leucine 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.<h4>Methods</h4>Higher overall e ...[more]

PMID: 31078521

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Project description:α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

Dataset Information

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

Publications

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

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