EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis.
EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis.
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DOI：
10.14814/phy2.12915
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发表时间：
2016-09
影响因子：
2.5
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Xiao X;Senavirathna LK;Gou X;Huang C;Liang Y;Liu L
成纤维细胞/肌成纤维细胞在纤维化灶中的积聚是特发性肺纤维化（IPF）的特征之一。zeste同源物2增强子（EZH 2）是多蛋白复合物polycomb抑制复合物2的催化组分，其参与组蛋白H3在赖氨酸27处的三甲基化。在这项研究中，我们研究了EZH 2在成纤维细胞向肌成纤维细胞分化中的作用和机制。我们发现EZH 2在IPF患者的肺和博莱霉素诱导的肺纤维化小鼠中上调。EZH 2的上调发生在肌成纤维细胞中。通过其抑制剂3-去氮普兰诺菌素A（DZNep）或shRNA抑制EZH 2可减少TGF-β1诱导的人肺成纤维细胞向肌成纤维细胞的分化，如肌成纤维细胞标志物α-平滑肌肌动蛋白和纤连蛋白的表达以及收缩性所示。DZNep抑制Smad 2/3核转位而不影响Smad 2/3磷酸化。DZNep治疗减弱了小鼠中博来霉素诱导的肺纤维化。我们的结论是，EZH 2通过增强Smad 2/3核转位诱导成纤维细胞分化为肌成纤维细胞。
The accumulation of fibroblasts/myofibroblasts in fibrotic foci is one of the characteristics of idiopathic pulmonary fibrosis (IPF). Enhancer of zeste homolog 2 (EZH2) is the catalytic component of a multiprotein complex, polycomb repressive complex 2, which is involved in the trimethylation of histone H3 at lysine 27. In this study, we investigated the role and mechanisms of EZH2 in the differentiation of fibroblasts into myofibroblasts. We found that EZH2 was upregulated in the lungs of patients with IPF and in mice with bleomycin‐induced lung fibrosis. The upregulation of EZH2 occurred in myofibroblasts. The inhibition of EZH2 by its inhibitor 3‐deazaneplanocin A (DZNep) or an shRNA reduced the TGF‐β1‐induced differentiation of human lung fibroblasts into myofibroblasts, as demonstrated by the expression of the myofibroblast markers α‐smooth muscle actin and fibronectin, and contractility. DZNep inhibited Smad2/3 nuclear translocation without affecting Smad2/3 phosphorylation. DZNep treatment attenuated bleomycin‐induced pulmonary fibrosis in mice. We conclude that EZH2 induces the differentiation of fibroblasts to myofibroblasts by enhancing Smad2/3 nuclear translocation.