Rotenone affects p53 transcriptional activity and apoptosis via targeting <scp>SIRT</scp>1 and H3K9 acetylation in <scp>SH</scp>‐<scp>SY</scp>5Y cells

<jats:title>Abstract</jats:title><jats:p>The protein deacetylase <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 has been recognized to exert its protective effect by directly deacetylasing histone and many other transcriptional factors including p53. However, the effect of <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 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 <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 level, and promoted p53 expression. Pre‐treatment with resveratrol, a <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 activator, could attenuate rotenone‐induced cell injury and p53 expression, whereas down‐regulation of <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 directly increased p53 expression. Moreover, chromatin immunoprecipitation experiments showed that <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 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 <jats:styled-content style="fixed-case">SIRT</jats:styled-content>1 and H3K9. This leads to nigrostriatal degeneration, the main pathogenic mechanism of motor features of Parkinson's disease. <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc13172-fig-0008-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> SIRT1, a deacetylase enzyme, has neuroprotective effects for Parkinson's disease via targeting various factors. Resveratrol activated SIRT1 can target H3K9 and regulate p53 gene expression at the transcriptional level, thus inhibiting p53 transcription to enhance neuroprtoection, alleviating rotenone induced dopaminergic neurodegeneration. We think these findings should provide a new strategy for the treatment of Parkinson's disease. </jats:p>