Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

Wasson, Christopher W.; Abignano, Giuseppina; Hermes, H.; Malaab, Maya; Ross, Rebecca; Jimenez, Sergio A.; Chang, Howard Y.; Feghali‐Bostwick, Carol; Galdo, Francesco Del

doi:10.1136/annrheumdis-2019-216542

Cited by 71 publications

(73 citation statements)

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“…Notch signalling is known to enhance expression of the transcription factor GLI2 [ 16 , 17 ], and HOTAIR is known to regulate Notch expression in fibroblasts [ 11 ]. Therefore, we first investigated whether HOTAIR regulates the expression of GLI2 in dermal fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

“…All inhibitors were reconstituted in DMSO and added to fibroblasts in complete media for 48 h at 37 °C in a 5% CO 2 atmosphere. The inhibitor concentrations were selected as they have been shown to efficiently block their respective pathways in SSc fibroblasts in previous studies [ 7 , 8 , 10 , 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…Upon ligand binding, the Notch receptor is cleaved by gamma secretases, which leads to the release of the Notch intracellular domain (NID). In turn, NID binds to the transcription factor CSL [ 13 ] and initiates transcription of a number of downstream transcription factors including Hes1 [ 14 ], which has previously been shown to be upregulated in SSc patient skin and fibroblasts [ 7 , 11 ]. Inhibition of Notch signalling blocks the expression of pro-fibrotic markers in SSc fibroblasts [ 7 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts

et al. 2020

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Objectives Systemic sclerosis (SSc) is characterised by tissue fibrosis of the major organs of the body including the skin, lungs and heart. We have previously reported that the lncRNA HOTAIR plays a central role in the activation of SSc myofibroblasts, the key cellular elements of fibrosis. HOTAIR induces fibroblast activation through H3K27me3-mediated activation of the Notch signalling pathway. Here we aimed to identify the signalling events downstream of Notch that drive SSc myofibroblast activation. Methods Patient fibroblasts were obtained from full-thickness forearm skin biopsies of 3 adult patients with SSc of recent onset. The lncRNA HOTAIR was expressed in healthy dermal fibroblasts by lentiviral transduction. Hedgehog signalling pathway was inhibited with GANT61 and GLI2 siRNA. Gamma secretase inhibitors RO4929097 and DAPT were used to block Notch signalling. GSK126 was used to inhibit Enhancer of Zeste 2 (EZH2). Results Overexpression of HOTAIR in dermal fibroblasts induced the expression of the Hedgehog pathway transcription factor GLI2. This is mediated by activation of Notch signalling following epigenetic downregulation of miRNA-34a expression. Inhibition of H3K27 methylation and Notch signalling reduced expression of GLI2 in HOTAIR-expressing fibroblasts as well as in SSc dermal fibroblasts. Importantly, the inhibition of GLI2 function using GANT61 or siRNA mitigates the pro-fibrotic phenotype induced by HOTAIR. Conclusions Our data indicates that GLI2 expression is stably upregulated in SSc myofibroblasts through HOTAIR and that GLI2 mediates the expression of pro-fibrotic markers downstream of Notch.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts

et al. 2020

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“…The increase in the number of myofibroblasts in vivo correlates with the disease severity of systemic sclerosis (SSc) and they display high levels of HOTAIR. Overexpression of HOTAIR in dermal fibroblasts induced an EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation [ 90 ]. HOTAIR upregulation also correlates with the progression of liver fibrosis.…”

Section: Hotair and Mirnas Interaction In Embryonic Development Anmentioning

confidence: 99%

Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases

Cantile

Bonito

Tracey

et al. 2021

Cancers

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LncRNAs are a class of non-coding RNAs mostly involved in regulation of cancer initiation, metastatic progression, and drug resistance, through participation in post-transcription regulatory processes by interacting with different miRNAs. LncRNAs are able to compete with endogenous RNAs by binding and sequestering miRNAs and thereby regulating the expression of their target genes, often represented by oncogenes. The lncRNA HOX transcript antisense RNA (HOTAIR) represents a diagnostic, prognostic, and predictive biomarker in many human cancers, and its functional interaction with miRNAs has been described as crucial in the modulation of different cellular processes during cancer development. The aim of this review is to highlight the relation between lncRNA HOTAIR and different microRNAs in human diseases, discussing the contribution of these functional interactions, especially in cancer development and progression.

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“…Furthermore, we found that MIAT acted as a sponge of miR-147a, and miR-147a directly targeted NKAP. Accumulating evidences have shown that lncRNAs regulate miRNA abundance by binding or chelating miRNA, and play the "sponge" role of lncRNAs, thus regulating a series of pathophysiological processes [ 43 ]. miR-147a has been reported to relate to non-small-cell lung cancer [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Silencing of lncRNA MIAT alleviates LPS-induced pneumonia via regulating miR-147a/NKAP/NF-κB axis

Liu

Song

et al. 2020

Aging

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Purpose: Pneumonia is a respiratory disease with an increasing incidence in recent years. More and more studies have revealed that lncRNAs can regulate the transcriptional expression of target genes at different stage. Herein, we aimed to explore the effect of lncRNA MIAT in LPS-induced pneumonia, and further illuminate the possible underlying mechanisms. Method and results: Mice were intraperitoneally injected with LPS, and the lung inflammation was evaluated. Microarray showed lncRNA MIAT was up-regulated in LPS-induced pulmonary inflammation. And qRT-PCR and FISH assay indicated that MIAT was increased in mice with LPS injection. Functional analysis showed sh-MIAT inhibited LPS-induced inflammation response, inhibited apoptosis level and protected lung function. As well, si-MIAT removed the injury of LPS on mouse lung epithelial TC-1 cells, and inhibited the activation of NF-κB signaling. Furthermore, MIAT acted as a sponge of miR-147a, and miR-147a directly targeted NKAP. Functionally, AMO-147a or NKAP remitted the beneficial effects of si-MIAT on LPS-induced inflammation response of TC-1 cells. Conclusion: Deletion of MIAT protected against LPS-induced lung inflammation via regulating miR-147a/NKAP, which might provide new insight for pneumonia treatment.

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Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

Cited by 71 publications

References 48 publications

Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts

Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts

Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases

Silencing of lncRNA MIAT alleviates LPS-induced pneumonia via regulating miR-147a/NKAP/NF-κB axis

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