Zeste同源物增强子2(enhancer of zeste homolog 2,EZH2)、胚胎外胚层发育蛋白(embryonic ectoderm development,EED)和zeste12同源蛋白抑制子(suppressor of zeste 12,SUZ12)是Polycomb蛋白家族PRC2复合体的核心元件。EZH2的经典作用为...Zeste同源物增强子2(enhancer of zeste homolog 2,EZH2)、胚胎外胚层发育蛋白(embryonic ectoderm development,EED)和zeste12同源蛋白抑制子(suppressor of zeste 12,SUZ12)是Polycomb蛋白家族PRC2复合体的核心元件。EZH2的经典作用为以PRC2复合体依赖的方式诱导组蛋白H3在K27位甲基化,从而引起基因沉默,参与调控细胞增殖、分化、衰老及肿瘤发生。本文介绍了EZH2的一些非经典功能,简述了EZH2作为一个多功能分子,不仅通过PRC2复合体依赖与非依赖的方式甲基化修饰一系列非组蛋白分子,影响其功能调节;还可与转录因子及辅因子直接相互作用,作为支架分子参与转录复合物组装,发挥转录抑制或转录激活作用。此外,EZH2还具有不依赖于转录的其他功能,如调控细胞迁移、信号通路活化、DNA复制和损伤修复、与RNA结合等。EZH2在经典和非经典作用之间的转换,与不同激酶和信号通路的调控有关。本文提示EZH2在生命活动中具有重要作用,其在不同生物学事件和疾病中的效应和调控方式有待进一步深入研究。展开更多
EZH2 （enhancer of zestehomolog 2） is a methyltransferase that induces histone H3 lysine 27 trimethyla-tion （ H3K27me3 ） and functions as an oncogenic factor in many cancer types. However, its rolein renal fibrogen...EZH2 （enhancer of zestehomolog 2） is a methyltransferase that induces histone H3 lysine 27 trimethyla-tion （ H3K27me3 ） and functions as an oncogenic factor in many cancer types. However, its rolein renal fibrogenesis remains to be explored. In this study, we found that EZH2 and H3K27me3 were highly expressed in the cultured renal fibroblastsand thefibrotic kidney from mice with unilateral ureteral obstruction and from humans withchronic kidney disease. Pharmacological inhibition of EZH2 with3-deazaneplanocin A（3-DZNeP） and GSK126, or silen- cing of EZH2 with its specific siRNA, inhibited serum-and TGF[31-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of oL-SMA in the obstructed kidney. Mechanistically,3-DZNeP inhibited expression of type I TGF-β1 receptor and phosphoryl- ation of Smad3, along with preservation of Smad-7 expression. 3-DZNeP treatment also suppressed phosphorylation of the EGF and PDGFβ receptors as well as STAT3 and ERK1/2, two signaling pathways associated with renal fi- brosis in the injured kidney. Moreover, EZH2 inhibition increased expression of PTEN, a protein tyrosine phospha- tase associated with the dephosphorylation of multiple tyrosine kinase receptors, in the kidney after ureteral ligation and in serum-stimulated renal interstitial fibroblasts. Finally, inhibition of PTEN reversed the antagonistic effect of 3-DZNeP on myofibroblast activation. These results uncovered the important role of EZH2in mediating activation of renal fibroblasts and the development of renal fibrosis through the activation of multiple profibrotic signaling path- ways. Targeted inhibition of EZH2 could therefore represent a novel therapy to treat chronic kidney disease.展开更多
文摘Zeste同源物增强子2(enhancer of zeste homolog 2,EZH2)、胚胎外胚层发育蛋白(embryonic ectoderm development,EED)和zeste12同源蛋白抑制子(suppressor of zeste 12,SUZ12)是Polycomb蛋白家族PRC2复合体的核心元件。EZH2的经典作用为以PRC2复合体依赖的方式诱导组蛋白H3在K27位甲基化,从而引起基因沉默,参与调控细胞增殖、分化、衰老及肿瘤发生。本文介绍了EZH2的一些非经典功能,简述了EZH2作为一个多功能分子,不仅通过PRC2复合体依赖与非依赖的方式甲基化修饰一系列非组蛋白分子,影响其功能调节;还可与转录因子及辅因子直接相互作用,作为支架分子参与转录复合物组装,发挥转录抑制或转录激活作用。此外,EZH2还具有不依赖于转录的其他功能,如调控细胞迁移、信号通路活化、DNA复制和损伤修复、与RNA结合等。EZH2在经典和非经典作用之间的转换,与不同激酶和信号通路的调控有关。本文提示EZH2在生命活动中具有重要作用,其在不同生物学事件和疾病中的效应和调控方式有待进一步深入研究。
文摘EZH2 （enhancer of zestehomolog 2） is a methyltransferase that induces histone H3 lysine 27 trimethyla-tion （ H3K27me3 ） and functions as an oncogenic factor in many cancer types. However, its rolein renal fibrogenesis remains to be explored. In this study, we found that EZH2 and H3K27me3 were highly expressed in the cultured renal fibroblastsand thefibrotic kidney from mice with unilateral ureteral obstruction and from humans withchronic kidney disease. Pharmacological inhibition of EZH2 with3-deazaneplanocin A（3-DZNeP） and GSK126, or silen- cing of EZH2 with its specific siRNA, inhibited serum-and TGF[31-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of oL-SMA in the obstructed kidney. Mechanistically,3-DZNeP inhibited expression of type I TGF-β1 receptor and phosphoryl- ation of Smad3, along with preservation of Smad-7 expression. 3-DZNeP treatment also suppressed phosphorylation of the EGF and PDGFβ receptors as well as STAT3 and ERK1/2, two signaling pathways associated with renal fi- brosis in the injured kidney. Moreover, EZH2 inhibition increased expression of PTEN, a protein tyrosine phospha- tase associated with the dephosphorylation of multiple tyrosine kinase receptors, in the kidney after ureteral ligation and in serum-stimulated renal interstitial fibroblasts. Finally, inhibition of PTEN reversed the antagonistic effect of 3-DZNeP on myofibroblast activation. These results uncovered the important role of EZH2in mediating activation of renal fibroblasts and the development of renal fibrosis through the activation of multiple profibrotic signaling path- ways. Targeted inhibition of EZH2 could therefore represent a novel therapy to treat chronic kidney disease.
