Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Cell Death Differ. 2011 Dec;18(12):1825-35. doi: 10.1038/cdd.2011.51. Epub 2011 May 6.
Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-κB (NF-κB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-κB activity. Further investigation showed that Zac1 inhibits NF-κB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-κB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.
组蛋白去乙酰化酶（HDAC）抑制剂是一类很有前途的抗癌试剂。它们能够诱导胚胎癌细胞（EC）凋亡。然而，其潜在的机制仍不清楚。在这里，我们表明锌指蛋白凋亡和细胞周期阻滞调节剂（Zac1）的表达增加与 HDAC 抑制剂诱导的 F9 和 P19 EC 细胞凋亡有关。通过染色质免疫沉淀分析，我们发现 Zac1 表达的增加是由 Zac1 启动子区域的组蛋白乙酰化介导的。Zac1 的敲低抑制了 HDAC 抑制剂诱导的细胞凋亡。此外，HDAC 抑制剂抑制核因子-κB（NF-κB）的活性，而 Zac1 的敲低消除了这种作用。一致地，Zac1 过表达抑制了细胞 NF-κB 的活性。进一步的研究表明，Zac1 通过与 p65 亚基的 C 端相互作用来抑制 NF-κB 的活性，从而抑制 p65 丝氨酸 468 和丝氨酸 536 残基的磷酸化。这些结果表明，Zac1 是 NF-κB 的一个组蛋白乙酰化调节抑制剂，它被诱导并参与了 HDAC 抑制剂介导的 EC 细胞凋亡。
