Expression of ESE-3 Isoforms in Immunogenic and Tolerogenic Human Monocyte-Derived Dendritic Cells

Sprater, Florian; Hovden, Arnt-Ove; Appel, Silke

doi:10.1371/journal.pone.0049577

Cited by 6 publications

(13 citation statements)

References 47 publications

(56 reference statements)

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“…18, 21 EHF has been demonstrated to function as a potential tumor suppressor gene in prostate cancer and esophageal squamous cell carcinoma (ESCC), 19, 22, 23 and be frequently downregulated by promoter methylation. 22 On the other hand, it is overexpressed in ovarian and mammary cancers 24, 25, 26 and may be a predictive marker for poor survival in ovarian cancer. 24, 25 However, the roles of EHF in gastric tumorigenesis are not fully understood.…”

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confidence: 99%

Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Shi

et al. 2016

Cell Death Dis

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The biological function of E26 transformation-specific (ETS) transcription factor EHF/ESE-3 in human cancers remains largely unknown, particularly gastric cancer. The aim of this study was to explore the role of EHF in tumorigenesis and its potential as a therapeutic target in gastric cancer. By using quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, we investigated the expression and copy number of EHF in a cohort of gastric cancers and control subjects. Specific EHF siRNAs was used to determine the biologic impacts and mechanisms of altered EHF expression in vitro and in vivo. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) assays were performed to identify its downstream targets. Our results demonstrated that EHF was significantly upregulated and frequently amplified in gastric cancer tissues as compared with control subjects. Moreover, EHF amplification was positively correlated with its overexpression and significantly associated with poor clinical outcomes of gastric cancer patients. We also found that EHF knockdown notably inhibited gastric cancer cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice and induced cell cycle arrest and apoptosis. Importantly, we identified EHF as a new HER2 transcription factor and the modulator of HER3 and HER4 in gastric cancer. Collectively, our findings suggest that EHF is a novel functional oncogene in gastric cancer by regulating the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases and may represent a potential prognostic marker and therapeutic target for this cancer.

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confidence: 99%

Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Shi

et al. 2016

Cell Death Dis

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“…Functionally, Ehf is a transcriptional repressor of several genes regulated by MAPK signaling with a dependency on an Ets binding site (29). Recently, Ehf has been reported to be involved in the development of monocyte-derived dendritic cells (30)(31)(32).…”

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confidence: 99%

The Transcription Factor Ehf Is Involved in TGF-β–Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells

Yamazaki

Nakano

Honjo

et al. 2015

The Journal of Immunology

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FcεRI, which is composed of α, β, and γ subunits, plays an important role in IgE-mediated allergic responses. TGF-β1 has been reported to suppress FcεRI and stem cell factor receptor c-Kit expression on mast cell surfaces and to suppress mast cell activation induced by cross-linking of FcεRI. However, the molecular mechanism by which these expressions and activation are suppressed by TGF-β1 remains unclear. In this study, we found that the expression of Ets homologous factor (Ehf), a member of the Ets family transcriptional factors, is upregulated by TGF-β/Smad signaling in mouse bone marrow–derived mast cells (BMMCs). Forced expression of Ehf in BMMCs repressed the transcription of genes encoding FcεRIα, FcεRIβ, and c-Kit, resulting in a reduction in cell surface FcεRI and c-Kit expression. Additionally, forced expression of Ehf suppressed FcεRI-mediated degranulation and cytokine production. Ehf inhibited the promoter activity of genes encoding FcεRIα, FcεRIβ, and c-Kit by binding to these gene promoters. Furthermore, the mRNA levels of Gata1, Gata2, and Stat5b were lower in BMMCs stably expressing Ehf compared with control cells. Because GATA-1 and GATA-2 are positive regulators of FcεRI and c-Kit expression, decreased expression of GATAs may be also involved in the reduction of FcεRI and c-Kit expression. Decreased expression of Stat5 may contribute to the suppression of cytokine production by BMMCs. In part, mast cell response to TGF-β1 was mimicked by forced expression of Ehf, suggesting that TGF-β1 suppresses FcεRI and c-Kit expression and suppresses FcεRI-mediated activation through upregulation of Ehf.

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“…Surprisingly, stimulation of the cells with LPS had only little effect on ESE‐3 mRNA levels (2‐fold increase compared with immature cells), while previous studies showed a more pronounced effect . One possible explanation could be the variability between donors already observed previously, which might be caused by differences in TLR4 expression levels.…”

Section: Discussionmentioning

confidence: 69%

“…One possible explanation for the difference in ESE‐3b levels in tolerogenic DCs is the choice of method used to generate the cells. In our previous study, we used a combination of dexamethasone and vitamin‐D3, and 15‐Deoxy‐Δ12,14‐prostaglandin J2, respectively, to generate tolerogenic DCs , while in the present study, different PPAR‐ γ agonists were used.…”

Section: Discussionmentioning

confidence: 99%

“…By analysing the expression of the different ESE‐3 isoforms in various moDC populations, we showed that ESE‐3 is expressed in two isoforms, ESE‐3a and ESE‐3b, with ESE‐3b being the main transcript , whereas isoform ESE‐3j was not detectable in any moDC population . Additionally, ESE‐3b was highly expressed in immunogenic moDCs, whereas only low ESE‐3b expression could be seen in tolerogenic moDCs .…”

Section: Introductionmentioning

confidence: 95%

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Activation of Peroxisome Proliferator‐activated Receptor Gamma Leads to Upregulation of ESE‐3 Expression in Human Monocyte‐derived Dendritic Cells

2013

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The transcription factor ESE-3 has been suggested to be involved in regulating the immunogenicity of human monocyte-derived dendritic cells (moDCs). While ESE-3 is not expressed in monocytes, it is upregulated during the differentiation of monocytes into dendritic cells (DCs) and highly expressed in immunogenic DCs while downregulated in tolerogenic DCs. Activation of peroxisome proliferator-activated receptor gamma (PPAR-c) during DC development has been shown to result in a rather tolerogenic cell population. In this study, we identified eight PPAR-c binding sites upstream of the ESE-3 gene. Activation of the PPAR-c pathway with synthetic PPAR-c ligands during moDC generation resulted in upregulation of ESE-3b expression on mRNA and protein level, phenotypic alterations and reduced capacity of the cells to stimulate allogeneic T cells. This could be inhibited by blocking the PPAR-c pathway with specific antagonists. Our results suggest PPAR-c to be involved in the regulation of ESE-3b expression during moDC development and that ESE-3 expression is not correlated with the immunogenicity of DCs.

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Expression of ESE-3 Isoforms in Immunogenic and Tolerogenic Human Monocyte-Derived Dendritic Cells

Cited by 6 publications

References 47 publications

Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

The Transcription Factor Ehf Is Involved in TGF-β–Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells

Activation of Peroxisome Proliferator‐activated Receptor Gamma Leads to Upregulation of ESE‐3 Expression in Human Monocyte‐derived Dendritic Cells

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