Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression.
Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression.
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DOI：
10.1038/onc.2010.51
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发表时间：
2010-05-27
期刊：
影响因子：
8
通讯作者：
Wang, Y.
中科院分区：
文献类型：
--
作者：
Li, P.;Wang, D.;Yao, H.;Doret, P.;Hao, G.;Shen, Q.;Qiu, H.;Zhang, X.;Wang, Y.;Chen, G.;Wang, Y.
已发现组蛋白Arg甲基化和Lys乙酰化协同调节p53靶基因的表达。肽基精氨酸脱亚胺酶4（PAD 4）是瓜氨酸化组蛋白精氨酸和单甲基精氨酸残基从而调节组蛋白Arg甲基化的酶。我们最近发现，PAD 4作为p53的辅阻遏物调节p53靶基因p21/WAF 1/CIP 1启动子的组蛋白Arg甲基化。然而，尚未测试组蛋白精氨酸瓜氨酸是否与其他组蛋白修饰协调以抑制转录。在这里，我们表明，HDAC 2和PAD 4通过不同的结构域与p53相互作用，同时与p21启动子调节基因表达。在DNA损伤后，PAD 4和HDAC 2从几个p53靶基因启动子（例如，p21、GADD 45和p21），同时在这些启动子处组蛋白Lys乙酰化和Arg甲基化增加。此外，PAD 4启动子关联和组蛋白Arg修饰受p53和HDAC活性调节。相比之下，HDAC 2启动子关联和组蛋白赖氨酸乙酰化受p53和PAD 4活性的影响较小。重要的是，PAD 4抑制剂Cl-脒和HDAC抑制剂SAHA在诱导p21、GADD 45和GADA表达以及以p53依赖性方式抑制癌细胞生长方面表现出累加效应。我们的研究结果揭示了组蛋白去乙酰化和瓜氨酸之间的重要串扰，表明PAD 4和HDAC 2抑制剂的组合作为癌症治疗的潜在策略。
Histone Arg methylation and Lys acetylation have been found to cooperatively regulate the expression of p53 target genes. Peptidylarginine deiminase 4 (PAD4) is an enzyme that citrullinates histone arginine and monomethyl-arginine residues thereby regulating histone Arg methylation. We have recently found that PAD4 serves as a p53 corepressor to regulate histone Arg methylation at the p53 target gene p21/WAF1/CIP1 promoter. However, it has not been tested whether histone Arg citrullination coordinates with other histone modifications to repress transcription. Here, we show that HDAC2 and PAD4 interact with p53 via distinct domains and simultaneously associate with the p21 promoter to regulate gene expression. After DNA damage, PAD4 and HDAC2 dissociate from several p53-target gene promoters (e.g., p21, GADD45, and PUMA) with a concomitant increase in histone Lys acetylation and Arg methylation at these promoters. Furthermore, PAD4 promoter association and histone Arg modifications are regulated by p53 and HDAC activity. In contrast, HDAC2 promoter association and histone Lys acetylation are affected by p53 and PAD4 activity at minor degrees. Importantly, PAD4 inhibitor Cl-amidine and HDAC inhibitor SAHA demonstrate additive effects in inducing p21, GADD45, and PUMA expression and inhibiting cancer cell growth in a p53-dependent manner. Our results unveil an important crosstalk between histone deacetylation and citrullination, suggesting that a combination of PAD4 and HDAC2 inhibitors as a potential strategy for cancer treatment.
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