组蛋白甲基转移酶2(SET and MYND domain-containing proteins 2, SMYD2)是SMYD家族成员,其功能是对组蛋白和非组蛋白进行甲基化修饰,调节下游的靶基因和信号通路,广泛参与肿瘤、炎症及免疫失调等疾病。近年来,恶性肿瘤的发病率呈逐年...组蛋白甲基转移酶2(SET and MYND domain-containing proteins 2, SMYD2)是SMYD家族成员,其功能是对组蛋白和非组蛋白进行甲基化修饰,调节下游的靶基因和信号通路,广泛参与肿瘤、炎症及免疫失调等疾病。近年来,恶性肿瘤的发病率呈逐年增高的趋势,严重影响患者的生活质量,给家庭和社会带来极大的经济负担。肿瘤发生的潜在机制在很大程度上仍不清楚,但越来越多的证据表明甲基化的异常调节与肿瘤发生密切相关。SMYD2参与多个信号通路的调控进而影响肿瘤干细胞、肿瘤细胞增殖与转移以及耐药等生物学特征。因此,本文对SMYD2在常见肿瘤中的作用机制进行综述,以期为SMYD2的机制研究及其抑制剂用于肿瘤治疗提供理论基础。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
文摘组蛋白甲基转移酶2(SET and MYND domain-containing proteins 2, SMYD2)是SMYD家族成员,其功能是对组蛋白和非组蛋白进行甲基化修饰,调节下游的靶基因和信号通路,广泛参与肿瘤、炎症及免疫失调等疾病。近年来,恶性肿瘤的发病率呈逐年增高的趋势,严重影响患者的生活质量,给家庭和社会带来极大的经济负担。肿瘤发生的潜在机制在很大程度上仍不清楚,但越来越多的证据表明甲基化的异常调节与肿瘤发生密切相关。SMYD2参与多个信号通路的调控进而影响肿瘤干细胞、肿瘤细胞增殖与转移以及耐药等生物学特征。因此,本文对SMYD2在常见肿瘤中的作用机制进行综述,以期为SMYD2的机制研究及其抑制剂用于肿瘤治疗提供理论基础。
文摘目的:探讨microRNA-377(miR-377)与组蛋白甲基转移酶SMYD3在肝癌中的表达规律及与肝癌的相关性.方法:利用实时定量PCR分别检测不同肝组织及肝细胞系中miR-377表达水平,应用实时定量PCR和Western blot分别检测不同肝组织及肝细胞系中SMYD3 mRNA和蛋白水平的表达情况.通过转染miR-377模拟物上调其在肝癌细胞株HepG2中表达后,应用实时定量PCR、Western blot分别检测转染前后HepG2中SMYD3 mRNA和蛋白表达的变化.结果:MiR-377 mRNA在人肝癌旁组织和肝癌组织中的表达较正常肝脏明显降低(0.331±0.059,0.139±0.064 vs 0.874±0.178,均P<0.05);在HepG2中的表达较L-02明显降低(0.145±0.021vs0.868±0.194,P<0.05).SMYD3 mRNA和蛋白质在人肝癌旁组织和肝癌组织中的表达较正常肝脏明显升高(mRNA:3.836±0.137,5.836±0.965vs1.235±0.332;蛋白:0.381±0.020,0.484±0.030vs0.252±0.015;均P<0.05).SMYD3 mRNA和蛋白质在肝癌细胞系HepG2中的表达较正常肝细胞系L-02明显升高(mRNA:0.845±0.047vs0.348±0.134;蛋白:0.575±0.008vs0.259±0.007,均P<0.05).转染miRNA-377模拟物上调HepG2中miR-377表达后转染组SMYD3 mRNA和蛋白表达较空白组和阴性对照组均明显下降(mRNA:0.125±0.010 vs 0.857±0.163,0.779±0.167;蛋白:0.092±0.026 vs 0.347±0.040,0.383±0.054,均P<0.05).结论:miRNA-377在肝癌中表达明显下调,其靶基因SMYD3表达上调;表达下调的miRNA-377丧失对SMYD3表达的抑制可能是肝癌发生的重要机制.
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.
