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EZH2-inhibitor DZNep enhances apoptosis of renal tubular epithelial cells in presence and absence of cisplatin

机译：Ezh2-抑制剂DZNEP在表现和不存在下增强肾小管上皮细胞的凋亡

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The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers. However, the role of EZH2 in nonneoplastic diseases, such as kidney diseases, is unknown and has been investigated. NRK-52E cells were treated with DZNep, a potent inhibitor of EZH2, with different concentrations and for different times to evaluate the apoptosis level of NRK-52E cells by Western blot and Flow cytometry analysis. The binding of EZH2 to the Deptor promoter was determined by ChIP?assay. The inhibition of EZH2 with 3-deazaneplanocin A (DZNep), a specific inhibitor of EZH2, led to the apoptosis of NRK-52E cells and the inhibition of mTORC1 and mTORC2 activity. A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region. Further experiments were performed to examine the effects of EZH2 inhibition on cisplatin-induced injured cells. Cisplatin induced the activation of mTORC1 and mTORC2 and apoptosis in NRK-52E cells, and DZNep inhibited mTORC1 and mTORC2 activity and aggravated cell apoptosis. These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells. The inhibition of EZH2 aggravated the cisplatin-induced injury in renal tubular cells by inactivating the mTOR complexes. The present study provides new insight into renal protection and suggests that EZH2 might be a target.
机译：Zeste同源物2（EZH2）的增强子是组蛋白甲基转移酶，并在许多关键基因的启动子中诱导组蛋白H3赖氨酸27（H3K27ME3）的三甲基化; EZH2充当转录压缩机，是几种癌症的表观遗传调节剂。然而，EZH2在非吞噬疾病（如肾脏疾病）中的作用是未知的并且已经研究过。将NRK-52E细胞用DZNEP，EZH2的有效抑制剂处理，具有不同浓度和不同时间，通过Western印迹和流式细胞术分析评估NRK-52E细胞的凋亡水平。通过芯片测定EZH2与去普罗斯启动子的结合α测定。 EZH2与3-甲烷平坦A（DZNEP），EZH2的特异性抑制剂的抑制导致NRK-52E细胞的凋亡和MTORC1和MTORC2活性的抑制。芯片测定表明，EzH2结合了去普罗斯的启动子区，MTORC1和MTORC2的内源抑制剂，并通过调节其启动子区中的H3K27ME3来调节除去剂的转录。进行进一步的实验以检查EZH2抑制对顺铂诱导的损伤细胞的影响。顺铂诱导在NRK-52E细胞中的MTORC1和MTORC2和细胞凋亡的激活，DZNEP抑制MTORC1和MTORC2活性和加重细胞凋亡。这些数据表明，EZH2抑制通过改变其启动子区中的H3K27ME3来增加去浦体的转录，随后抑制MTORC1和MTORC2活性，下调凋亡抑制基因的表达，最终导致肾小管细胞的凋亡。 EZH2的抑制通过灭活MTOR络合物使得肾小管细胞中的顺铂诱导的损伤加剧。本研究提供了对肾保护的新洞察力，并表明EZH2可能是目标。

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