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CCAAT/enhancer binding protein ? induces motility and invasion of glioblastoma cells through transcriptional regulation of the calcium binding protein S100A4.

ABSTRACT: We have previously shown that decreased expression of CCAAT/enhancer binding protein ? (C/EBP?) inhibits the growth of glioblastoma cells and diminishes their transformation capacity and migration. In agreement with this, we showed that C/EBP? depletion decreases the mRNA levels of different genes involved in metastasis and invasion. Among these, we found S100 calcium binding protein A4 (S100A4) to be almost undetectable in glioblastoma cells deficient in C/EBP?. Here, we have evaluated the possible role of S100A4 in the observed effects of C/EBP? in glioblastoma cells and the mechanism through which S100A4 levels are controlled by C/EBP?. Our results show that C/EBP? suppression significantly reduced the levels of S100A4 in murine GL261 and human T98G glioblastoma cells. By employing an S100A4-promoter reporter, we observed a significant induction in the transcriptional activation of the S100A4 gene by C/EBP?. Furthermore, overexpression of S100A4 in C/EBP?-depleted glioblastoma cells reverses the enhanced migration and motility induced by this transcription factor. Our data also point to a role of S100A4 in glioblastoma cell invasion and suggest that the C/EBP? gene controls the invasive potential of GL261 and T98G cells through direct regulation of S100A4. Finally, this study indicates a role of C/EBP? on the maintenance of the stem cell population present in GL261 glioblastoma cells.

SUBMITTER: Aguilar-Morante D

PROVIDER: S-EPMC4414196 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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CCAAT/enhancer binding protein β induces motility and invasion of glioblastoma cells through transcriptional regulation of the calcium binding protein S100A4.

Aguilar-Morante Diana D Morales-Garcia Jose A JA Santos Angel A Perez-Castillo Ana A

Oncotarget 20150201 6

We have previously shown that decreased expression of CCAAT/enhancer binding protein β (C/EBPβ) inhibits the growth of glioblastoma cells and diminishes their transformation capacity and migration. In agreement with this, we showed that C/EBPβ depletion decreases the mRNA levels of different genes involved in metastasis and invasion. Among these, we found S100 calcium binding protein A4 (S100A4) to be almost undetectable in glioblastoma cells deficient in C/EBPβ. Here, we have evaluated the poss ...[more]

PMID: 25738360

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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 ? induces motility and invasion of glioblastoma cells through transcriptional regulation of the calcium binding protein S100A4.

Publications

CCAAT/enhancer binding protein β induces motility and invasion of glioblastoma cells through transcriptional regulation of the calcium binding protein S100A4.

Similar Datasets

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