[PMID]: | 28884479 |
[Au] Autor: | Yang TY; Teng CJ; Lin TC; Chen KC; Hsu SL; Wu CC |
[Ad] Endereço: | Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 407, Taiwan, Republic of China. |
[Ti] Título: | Transcriptional repression of Aurora-A gene by wild-type p53 through directly binding to its promoter with histone deacetylase 1 and mSin3a. |
[So] Source: | Int J Cancer;142(1):92-108, 2018 Jan 01. |
[Is] ISSN: | 1097-0215 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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. |
[Mh] Termos MeSH primário: |
Adenocarcinoma/genética Aurora Quinase A/biossíntese Regulação Neoplásica da Expressão Gênica/genética Neoplasias Pulmonares/genética Proteína Supressora de Tumor p53/metabolismo
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[Mh] Termos MeSH secundário: |
Adenocarcinoma/mortalidade Aurora Quinase A/genética Linhagem Celular Tumoral Histona Desacetilase 1/genética Histona Desacetilase 1/metabolismo Seres Humanos Estimativa de Kaplan-Meier Neoplasias Pulmonares/mortalidade Regiões Promotoras Genéticas/genética Transcrição Genética/genética
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Tumor Suppressor Protein p53); EC 2.7.11.1 (AURKA protein, human); EC 2.7.11.1 (Aurora Kinase A); EC 3.5.1.98 (HDAC1 protein, human); EC 3.5.1.98 (Histone Deacetylase 1) |
[Em] Mês de entrada: | 1711 |
[Cu] Atualização por classe: | 171128 |
[Lr] Data última revisão:
| 171128 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170909 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1002/ijc.31035 |
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