EZH2‐mediated repression of Dkk1 promotes hepatic stellate cell activation and hepatic fibrosis

Yang, Yang; Chen, Xiaoxia; Li, Wanxia; Wu, Xiaoqin; Huang, Cheng; Xie, Juan; Zhao, Yong; Meng, Xiao‐Ming; Li, Jun

doi:10.1111/jcmm.13153

Cited by 50 publications

(36 citation statements)

References 29 publications

(35 reference statements)

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“…In conclusion, it is important to note that epigenetic regulators, including EZH2, have described roles in other liver cell types beyond cholangiocytes . In fact, our group and others have previously shown a pro‐fibrotic role for EZH2 in HSCs .…”

Section: Discussionmentioning

confidence: 62%

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

et al. 2019

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During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF-β). The result is an epigenetically regulated transcriptional program leading to a pro-fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF-β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF-β. Ingenuity pathway analysis identified "HSC Activation" as the highly up-regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF-β response. EZH2 overexpression suppressed TGF-β-induced FN protein in vitro, suggesting FN as a direct target of EZH2-based repression. Chromatin immunoprecipitation assays identified an FN promoter element in which EZH2-mediated tri-methylation of lysine 27 on histone 3 is diminished by TGF-β. TGF-β also caused a 50% reduction in EZH2 protein levels. Proteasome inhibition rescued EZH2 protein and led to reduced FN production. Immunoprecipitation followed by mass spectrometry identified ubiquitin protein ligase E3 component N-recognin 4 in complex with EZH2, which was validated by western blotting in vitro. Ubiquitin mutation studies suggested K63-based ubiquitin linkage and chain elongation on EZH2 in response to TGF-β. A deletion mutant of EZH2, lacking its N-terminal domain, abrogates both TGF-β-stimulated EZH2 degradation and FN release. In vivo, cholangiocyte-selective knockout of EZH2 exacerbates bile duct ligation-induced fibrosis whereas MDR2 -/mice are protected from fibrosis by the proteasome inhibitor bortezomib. Conclusion: TGF-β regulates proteasomal degradation of EZH2 through N-terminal, K63-linked ubiquitination in cholangiocytes and activates transcription of a fibrogenic gene program that supports biliary fibrosis.

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Section: Discussionmentioning

confidence: 62%

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

et al. 2019

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“…They showed that EZH2 may contribute to peroxisome proliferator-activated receptor γ transcriptional silencing in a relay pathway along with methyl CpG binding protein 2 and microRNA132. It also has been reported that EZH2-mediated repression of Dkk-1 may promote activation of the Wnt/β-catenin pathway, 29 which has been shown to contribute to HSC transdifferentiation. 30 Our results consistently confirm the profibrotic role of EZH2 in vitro and in vivo, corroborating its potential as a target for antifibrotic therapy.…”

Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis

Martín-Mateos

Assuncao

Arab

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsTransdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-β and PDGF signaling pathways.MethodsWe performed a transcriptomic comparison of HSCs treated with TGF-β or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators.ResultsEnhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-β but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-β–induced fibronectin, collagen 1α1, and α-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-β–treated cells. Finally, we conducted in vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and α-smooth muscle actin/collagen protein assays.ConclusionsTGF-β and PDGF share redundant and distinct transcriptomic targets, with the former predominating in HSC activation. The EZH2 histone methyltransferase is preferentially involved in the TGF-β as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-β–treated HSCs and reduces liver fibrosis in vivo. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE119606 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606)

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“…The profibrogenic role of the Wnt/β‐catenin signaling pathway in endometriosis has recently been reported . EZH2 can also suppress Dkk1, a negative regulator of the Wnt/β‐catenin signaling, inducing fibrosis . Again, Dkk1 expression is reported to be reduced in endometriosis …”

Section: Mutations Of Cancer Driver Genes In Endometriosis and Their mentioning

confidence: 97%

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

Guo

2018

Reprod Medicine & Biology

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BackgroundOne recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation.MethodsExtensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review.ResultsAll six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings.ConclusionsGiven that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.

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EZH2‐mediated repression of Dkk1 promotes hepatic stellate cell activation and hepatic fibrosis

Cited by 50 publications

References 29 publications

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

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