Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, Pennsylvania State University, University Park, PA 16802, USA.
Oncogene. 2010 May 27;29(21):3153-62. doi: 10.1038/onc.2010.51. Epub 2010 Mar 1.
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 histone deacetylase (HDAC2) and PAD4 interact with p53 through 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 (for example, 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 suberoylanilide hydroxamic acid show 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.
组蛋白精氨酸甲基化和赖氨酸乙酰化已被发现协同调节 p53 靶基因的表达。肽基精氨酸脱亚氨酶 4（PAD4）是一种使组蛋白精氨酸和单甲基精氨酸残基瓜氨酸化的酶，从而调节组蛋白精氨酸甲基化。我们最近发现 PAD4 作为 p53 辅阻遏物调节 p53 靶基因 p21/WAF1/CIP1 启动子处的组蛋白精氨酸甲基化。然而，尚未检测组蛋白精氨酸瓜氨酸化是否与其他组蛋白修饰协同抑制转录。在这里，我们表明组蛋白去乙酰化酶（HDAC2）和 PAD4 通过不同的结构域与 p53 相互作用，并同时与 p21 启动子结合以调节基因表达。在 DNA 损伤后，PAD4 和 HDAC2 从几个 p53 靶基因启动子（例如 p21、GADD45 和 PUMA）解离，同时伴随着这些启动子处组蛋白赖氨酸乙酰化和精氨酸甲基化的增加。此外，PAD4 启动子结合和组蛋白精氨酸修饰受 p53 和 HDAC 活性的调节。相比之下，HDAC2 启动子结合和组蛋白赖氨酸乙酰化受 p53 和 PAD4 活性的影响较小。重要的是，PAD4 抑制剂 Cl-amidine 和 HDAC 抑制剂 suberoylanilide hydroxamic acid 以 p53 依赖性方式在诱导 p21、GADD45 和 PUMA 表达和抑制癌细胞生长方面具有相加作用。我们的结果揭示了组蛋白去乙酰化和瓜氨酸化之间的重要串扰，表明 PAD4 和 HDAC2 抑制剂的联合使用可能是癌症治疗的一种策略。
