Impairment of p53 acetylation by EWS-Fli1 chimeric protein in Ewing Family Tumors
Impairment of p53 acetylation by EWS-Fli1 chimeric protein in Ewing Family Tumors
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尤文家族肿瘤中 EWS-Fli1 嵌合蛋白对 p53 乙酰化的损害
DOI：
10.1016/j.canlet.2012.01.018
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发表时间：
2012-07-01
期刊：
影响因子：
9.7
通讯作者：
Zhu, Yue
中科院分区：
文献类型：
--
作者：
Li, Yan;Li, Xu;Zhu, Yue
染色体易位t（11;22）（q24;q12）产生EWS-Fli 1融合基因，其有助于尤文家族肿瘤（EFT）的发展。先前的研究已经显示EWS-Fli 1嵌合蛋白沉默p53活性的能力。在EFTs细胞中，EWS-Fli 1的引入显著抑制p300介导的p53在Lys-382的乙酰化，并且通过小干扰RNA（siRNA）去除EWS-Fli 1蛋白促进其响应DNA损伤。此外，EWS-Fli 1对p53的去乙酰化抑制其转录活性并增强mdm 2介导的p53降解。另一方面，免疫沉淀研究表明，EWS-Fli 1的N端区域与组蛋白去乙酰化酶1（HDAC 1）结合，与p53形成复合物，敲除HDAC 1蛋白后，EFTs细胞中p53 Lys-382的表达恢复，而HDAC 2和HDAC 3蛋白表达恢复。HDAC 1的过表达也显著抑制了p53的转录活性。HDAC的药物抑制剂阿司他丁A（TSA）促进p53-p300相互作用和p53 Lys-382募集到其靶基因p21和Puma的启动子区，从而诱导细胞凋亡和稳定p53在Lys-382处的乙酰化以及上调p21和Puma，这在敲低p53表达后在EFTs细胞中受损。我们的数据表明EWS-Fli 1可能通过HDAC 1的募集使p53去乙酰化以抑制其转录功能和蛋白质稳定性。这些结果可能为EWS-Fli 1阻断p53通路在EFTs发病中的作用提供了新的分子机制。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
The chromosomal translocation t(11;22)(q24;q12) yields the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Previous studies have shown the ability of EWS-Fli1 chimeric protein to silence p53 activity. Here we demonstrate that the introduction of EWS-Fli1 significantly inhibited p300-mediated acetylation of p53 at Lys-382 and depletion of EWS-Fli1 protein by small interfering RNAs (siRNA) in EFTs cells facilitated it in response to DNA damage, Furthermore, the deacetylation of p53 by EWS-Fli1 suppressed its transcriptional activity and enhanced mdm2-mediated p53 degradation. On the other hand, immunoprecipitation study shows that N-terminal region of EWS-Fli1 associated with histone deacetylase 1 (HDAC1) to forms a complex with p53.Knockdown of HDAC1, but not HDAC2 or HDAC3 protein restored the expression of p53 Lys-382 in EFTs cells. Overexpression of HDAC1 also significantly inhibited p53 transcriptional activity. Pharmacologic inhibitor of HDAC, trichostatin A (TSA) promoted p53-p300 interaction and recruitment of p53 Lys-382 to promoter regions of its target genes p21 and Puma, consequently inducing apoptosis and stabilizing the acetylation of p53 at Lys-382 together with the upregulation of p21 and Puma, which were impaired in EFTs cells after the knockdown of p53 expression. Our data indicate EWS-Fli1 might deacetylate p53 to inhibit its transcriptional function and protein stability via the recruitment of HDAC1. These results might elucidate a novel molecular mechanism about the abrogation of p53 pathway by EWS-Fli1 in EFTs pathogenesis. (C) 2012 Elsevier Ireland Ltd. All rights reserved.