Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma.
Animals
Bleomycin
/ toxicity
Cell Movement
/ genetics
Disease Models, Animal
Endothelial Cells
/ metabolism
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Epigenetic Repression
/ genetics
Female
Fibroblasts
/ metabolism
Fibrosis
/ chemically induced
Gene Expression Regulation
/ genetics
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Male
Membrane Proteins
/ genetics
Methylation
Mice
Microfilament Proteins
/ genetics
Neovascularization, Physiologic
Receptors, Notch
/ genetics
Scleroderma, Diffuse
/ genetics
Signal Transduction
EZH2
Scleroderma
angiogenesis
epigenetics
fibrosis
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
26 02 2019
26 02 2019
Historique:
pubmed:
14
2
2019
medline:
3
5
2019
entrez:
14
2
2019
Statut:
ppublish
Résumé
Scleroderma (SSc) is a complex disease that involves activation of the immune system, vascular complications, and tissue fibrosis. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) mediates trimethylation of lysine 27 of histone 3 (H3K27me3), which acts as a repressive epigenetic mark. Both EZH2 and H3K27me3 were elevated in SSc dermal fibroblasts and endothelial cells compared with healthy controls. EZH2 inhibitor DZNep halted fibrosis both in vitro and in vivo. In SSc fibroblasts, DZNep dose-dependently reduced the expression of profibrotic genes and inhibited migratory activity of SSc fibroblasts. We show that epigenetic dysregulation and overexpression of LRRC16A explains EZH2-mediated fibroblast migration in SSc. In endothelial cells, inhibition of EZH2 restored normal angiogenesis in SSc via activating the Notch pathway, specifically by up-regulating the Notch ligand DLL4. Our results demonstrate that overexpression of EZH2 in SSc fibroblasts and endothelial cells is profibrotic and antiangiogenic. Targeting EZH2 or EZH2-regulated genes might be of therapeutic potential in SSc.
Identifiants
pubmed: 30755532
pii: 1813006116
doi: 10.1073/pnas.1813006116
pmc: PMC6397533
doi:
Substances chimiques
CARMIL1 protein, human
0
Intracellular Signaling Peptides and Proteins
0
Membrane Proteins
0
Microfilament Proteins
0
Receptors, Notch
0
delta protein
0
Bleomycin
11056-06-7
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3695-3702Subventions
Organisme : NIAMS NIH HHS
ID : T32 AR007080
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR070148
Pays : United States
Organisme : NCRR NIH HHS
ID : P20 RR015577
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI110502
Pays : United States
Organisme : NIAMS NIH HHS
ID : K24 AR063120
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI110557
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI097134
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007413
Pays : United States
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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