Inhibition of EZH2 Prevents Fibrosis and Restores Normal Angiogenesis in Scleroderma

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 Feb 14

PMID 30755532

Citations 51

Authors

Pei-Suen Tsou

Phillip Campbell

M Asif Amin

Patrick Coit

Shaylynn Miller

David A Fox

Dinesh Khanna

Amr H Sawalha

Affiliations

Soon will be listed here.

Abstract

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.

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