Enhancer of zeste homolog-2 (EZH2) methyltransferase regulates transgelin/smooth muscle-22α expression in endothelial cells in response to interleukin-1β and transforming growth factor-β2

Maleszewska, Monika; Gjaltema, Rutger A. F.; Krenning, Guido; Harmsen, Martin C.

doi:10.1016/j.cellsig.2015.04.008

Cited by 60 publications

(44 citation statements)

References 39 publications

(57 reference statements)

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“…Interestingly, inflammatory cytokines, such as TNF-α or IL-1β, are not only NFkB activators, but also its downstream transcriptional targets [23,26]. ADA treatment increased the expression of IL1B and TNFA genes by 73.3 ± 20.8- and 5.9 ± 0.6-fold, respectively (p < 0.0005; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, excess SAH suppresses EZH2, decreasing the global levels of the repressive H3K27me3 mark. Based on these results, we believe that EZH2 suppression promotes the expression of inflammatory cytokines, such as IL-1β, due to a decrease of the epigenetic mark H3K27me3 at the IL1B promoter [16,26]. Up-regulation of IL-1β may promote the continued stimulation of the NFkB pathway via activation of the IL-1β receptor.…”

Section: Discussionmentioning

confidence: 99%

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S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

Barroso

Kao

Blom

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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S-Adenosylhomocysteine (SAH) can induce endothelial dysfunction and activation, contributing to atherogenesis; however, its role in the activation of the inflammatory mediator NFkB has not been explored. Our aim was to determine the role of NFkB in SAH-induced activation of endothelial cells. Furthermore, we examined whether SAH, as a potent inhibitor of S-adenosylmethionine-dependent methyltransferases, suppresses the function of EZH2 methyltransferase to contribute to SAH-induced endothelial cell activation. We found that excess SAH increases the expression of adhesion molecules and cytokines in human coronary artery endothelial cells. Importantly, this up-regulation was suppressed in cells expressing a dominant negative form of the NFkB inhibitor, IkB. Moreover, SAH accumulation triggers the activation of both the canonical and non-canonical NFkB pathways, decreases EZH2, and reduces histone 3 lysine 27 trimethylation. EZH2 knockdown recapitulated the effects of excess SAH on endothelial activation, i.e., it induced NFkB activation and the subsequent up-regulation of adhesion molecules and cytokines. Our findings suggest that suppression of the epigenetic regulator EZH2 by excess SAH may contribute to NFkB activation and the consequent vascular inflammatory response. These studies unveil new targets of SAH regulation, demonstrating that EZH2 suppression and NFkB activation mediated by SAH accumulation may contribute to its adverse effects in the vasculature.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

Barroso

Kao

Blom

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In this model, EZH2 inhibitors prevented Oct4/Sox2/Klf4/c-Myc induced transformation of fibroblasts into iPSCs [31]. Likewise, it has been shown that inhibition of EZH2 augments the expression of transgelin/smooth muscle-22α, a mesenchymal marker, in response to TGF-β in endothelial cells [32]. Loss of EZH2 in the lung epithelium resulted in defective epithelial layer differentiation and alveoli formation [33].…”

Section: Discussionmentioning

confidence: 99%

EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells

et al. 2016

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Cancer cells acquire essential characteristics for metastatic dissemination through the process of epithelial-to-mesenchymal transition (EMT), which is regulated by gene expression and chromatin remodeling changes. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3) to repress gene transcription. Here we report the functional roles of EZH2-catalyzed H3K27me3 during EMT in ovarian cancer (OC) cells. TGF-β-induced EMT in SKOV3 OC cells was associated with decreased levels of EZH2 and H3K27me3 (P<0.05). These effects were delayed (~72 h relative to EMT initiation) and coincided with increased (>15-fold) expression of EMT-associated transcription factors ZEB2 and SNAI2. EZH2 knockdown (using siRNA) or enzymatic inhibition (by GSK126) induced EMT-like changes in OC cells. The EMT regulator ZEB2 was upregulated in cells treated with either approach. Furthermore, TGF-β enhanced expression of ZEB2 in EZH2 siRNA- or GSK126-treated cells (P<0.01), suggesting that H3K27me3 plays a role in TGF-β-stimulated ZEB2 induction. Chromatin immunoprecipitation assays confirmed that TGF-β treatment decreased binding of EZH2 and H3K27me3 to the ZEB2 promoter (P<0.05). In all, these results demonstrate that EZH2, by repressing ZEB2, is required for the maintenance of an epithelial phenotype in OC cells.

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“…In cardiovascular wound healing, fibrosis coincides with inflammation. In fact, EndMT is synergized by TGF‐β2 and IL‐1β . Heart failure is also associated with pro‐fibrotic stimuli by members of the TGF‐β superfamily, inflammation and reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

Adipose tissue–derived stromal cells’ conditioned medium modulates endothelial‐mesenchymal transition induced by IL‐1β/TGF‐β2 but does not restore endothelial function

Liguori

Moreira

et al. 2019

Cell Proliferation

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Objectives Endothelial cells undergo TGF‐β–driven endothelial‐mesenchymal transition (EndMT), representing up to 25% of cardiac myofibroblasts in ischaemic hearts. Previous research showed that conditioned medium of adipose tissue–derived stromal cells (ASC‐CMed) blocks the activation of fibroblasts into fibrotic myofibroblasts. We tested the hypothesis that ASC‐CMed abrogates EndMT and prevents the formation of adverse myofibroblasts. Materials and methods Human umbilical vein endothelial cells (HUVEC) were treated with IL‐1β and TGF‐β2 to induce EndMT, and the influence of ASC‐CMed was assessed. As controls, non‐treated HUVEC or HUVEC treated only with IL‐1β in the absence or presence of ASC‐CMed were used. Gene expression of inflammatory, endothelial, mesenchymal and extracellular matrix markers, transcription factors and cell receptors was analysed by RT‐qPCR. The protein expression of endothelial and mesenchymal markers was evaluated by immunofluorescence microscopy and immunoblotting. Endothelial cell function was measured by sprouting assay. Results IL‐1β/TGF‐β2 treatment induced EndMT, as evidenced by the change in HUVEC morphology and an increase in mesenchymal markers. ASC‐CMed blocked the EndMT‐related fibrotic processes, as observed by reduced expression of mesenchymal markers TAGLN (P = 0.0008) and CNN1 (P = 0.0573), as well as SM22α (P = 0.0501). The angiogenesis potential was impaired in HUVEC undergoing EndMT and could not be restored by ASC‐CMed. Conclusions We demonstrated that ASC‐CMed reduces IL‐1β/TGF‐β2‐induced EndMT as observed by the loss of mesenchymal markers. The present study supports the anti‐fibrotic effects of ASC‐CMed through the modulation of the EndMT process.

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Enhancer of zeste homolog-2 (EZH2) methyltransferase regulates transgelin/smooth muscle-22α expression in endothelial cells in response to interleukin-1β and transforming growth factor-β2

Cited by 60 publications

References 39 publications

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells

Adipose tissue–derived stromal cells’ conditioned medium modulates endothelial‐mesenchymal transition induced by IL‐1β/TGF‐β2 but does not restore endothelial function

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