Rotenone affects p53 transcriptional activity and apoptosis via targeting SIRT1 and H3K9 acetylation in SH-SY5Y cells
Rotenone affects p53 transcriptional activity and apoptosis via targeting SIRT1 and H3K9 acetylation in SH-SY5Y cells
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鱼藤酮通过靶向 SH-SY5Y 细胞中 SIRT1 和 H3K9 乙酰化影响 p53 转录活性和细胞凋亡
DOI：
10.1111/jnc.13172
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发表时间：
2015-08-01
影响因子：
4.7
通讯作者：
Wu, Yun-Cheng
中科院分区：
文献类型：
--
作者：
Feng, Ya;Liu, Te;Wu, Yun-Cheng
蛋白质脱乙酰基酶SIRT1已被认为通过直接脱乙酰化组蛋白和包括p53在内的许多其他转录因子来发挥其保护作用。然而，SIRT1在转录水平上对p53表达的影响仍有待阐明。在这项研究中，我们发现鱼藤酮处理降低细胞活力，诱导凋亡，降低SIRT1水平，促进p53表达。白藜芦醇预处理，SIRT1激活剂，可以减弱鱼藤酮诱导的细胞损伤和p53的表达，而SIRT1的下调直接增加p53的表达。此外，染色质免疫沉淀实验表明，SIRT1结合到p53启动子区域内的H3K9，这种结合导致H3K9乙酰化降低和H3K9三甲基化增加，从而抑制p53基因转录。总之，我们的数据表明鱼藤酮通过靶向SIRT1和H3K9促进p53转录和凋亡。这导致黑质纹状体变性，这是帕金森病运动特征的主要致病机制。
The protein deacetylase SIRT1 has been recognized to exert its protective effect by directly deacetylasing histone and many other transcriptional factors including p53. However, the effect of SIRT1 on p53 expression at the transcriptional level still remains to be elucidated. In this study, we found that rotenone treatment decreased cell viability, induced apoptosis, reduced SIRT1 level, and promoted p53 expression. Pre-treatment with resveratrol, a SIRT1 activator, could attenuate rotenone-induced cell injury and p53 expression, whereas down-regulation of SIRT1 directly increased p53 expression. Moreover, chromatin immunoprecipitation experiments showed that SIRT1 bound to H3K9 within the p53 promoter region, and this binding resulted in decreased H3K9 acetylation and increased H3K9 tri-methylation, thereby inhibiting p53 gene transcription. In conclusion, our data indicate that rotenone promotes p53 transcription and apoptosis through targeting SIRT1 and H3K9. This leads to nigrostriatal degeneration, the main pathogenic mechanism of motor features of Parkinson's disease.