Transcriptional repression of Aurora-A gene by wild-type p53 through directly binding to its promoter with histone deacetylase 1 and mSin3a

Abstract

In this study, we firstly showed that p53 transcriptionally represses Aurora-A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay indicated that p53 physically bound to the Aurora-A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora-A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides -360 to -354 (CCTGCCC), upstream of the Aurora-A transcriptional start site, was responsible for the p53-mediated repression. Mutation within this site disrupted its interaction with p53, mSin3a and HDAC1, as well as attenuated the repressive effect of p53 on Aurora-A promoter activity. Treatment with trichostatin A (TSA), a HDAC1 inhibitor, disrupted the interaction of p53-HDAC1-mSin3a complex with the nucleotides -365∼-345 region, and enhanced the Aurora-A promoter activity and gene expression. Additionally, knockdown of p53 or mSin3a also drastically blocked the formation of p53-HDAC1-mSin3a repressive complex onto this promoter region and elevated the Aurora-A promoter activity and gene expression. Moreover, the p53-HDAC1-mSin3a repressive complex also involved in the inhibition of Aurora-A gene expression upon cisplatin treatment. Finally, the clinical investigation showed that Aurora-A and p53 exhibited an inverse correlation in both the expression level and prognostic status and the low p53/high Aurora-A showed the poorest prognosis of NSCLC patients. Our findings showed novel regulatory mechanisms of p53 in regulating Aurora-A gene expression in NSCLC cells.

Many types of cancer feature a boost in production of the kinase Aurora-A, and several studies have implicated the protein in transformation and tumorigenesis. Some evidence suggests that p53 affects Aurora-A expression, and in this study, the authors set out to describe that relationship. They found that p53 binds directly to the Aurora-A promoter, repressing transcription. Next, they showed that treatment with trichostatin A thwarts this repression, allowing Aurora-A transcription to proceed. Clinical investigation revealed that lung cancer patients with low p53 and high Aurora-A expression had the worst prognosis. This article is protected by copyright. All rights reserved.

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