GeneCellPharm Corporation, 375 Munjeong 2(i)-dong, Songpa-gu Seoul, 05836, Republic of Korea.
Research Institute for Molecular-Targeted Drugs, Department of Cosmetics Engineering, Konkuk University, Seoul, 05029, Republic of Korea.
Biochem Biophys Res Commun. 2019 Sep 17;517(2):353-358. doi: 10.1016/j.bbrc.2019.07.052. Epub 2019 Jul 26.
HDAC3, one of the class I histone deacetylase modulates epigenetic landscape through histone modification. HDAC3 also interacts with non-histone proteins including p53 for deacetylation. Moreover, HDAC3 serves as a transcriptional repressor, interacting with NCor1/SMRT complex. Although HDAC3 plays a critical role for cellular homeostasis, regulatory mechanism of HDAC3 have been poorly understood. Here we report a novel regulatory mechanism of HDAC3 about its monoubiquitination and stabilization by Mdm2. HDAC3 levels were increased by ectopic expression of Mdm2 and decreased by Mdm2 ablation in various cell lines. We found that Mdm2 directly interacts with HDAC3 and induces HDAC3 protein levels without alteration of mRNA levels. Ectopic expression of wild type but not RING mutant of Mdm2 increased HDAC3 monoubiquitination. In addition, MdmX is beneficial for mdm2-mediated HDAC3 regulation. Ablation of Mdm2 and Mdm2/MdmX decreased cell migration along with the decrease of HDAC3 levels. These data provide an evidence that Mdm2 positively regulates HDAC3 monoubiquitination and stability.
HDAC3 是 I 类组蛋白去乙酰化酶之一，通过组蛋白修饰调节表观遗传景观。HDAC3 还与非组蛋白蛋白相互作用，包括 p53 进行去乙酰化。此外，HDAC3 作为转录抑制剂，与 NCor1/SMRT 复合物相互作用。虽然 HDAC3 对细胞内稳态起着至关重要的作用，但 HDAC3 的调节机制尚未得到很好的理解。在这里，我们报告了一种关于 Mdm2 对 HDAC3 的单泛素化和稳定作用的新型调节机制。在各种细胞系中，Mdm2 的异位表达增加了 HDAC3 的水平，而 Mdm2 的缺失减少了 HDAC3 的水平。我们发现 Mdm2 直接与 HDAC3 相互作用，并在不改变 mRNA 水平的情况下诱导 HDAC3 蛋白水平升高。野生型而非 RING 突变型 Mdm2 的异位表达增加了 HDAC3 的单泛素化。此外，MdmX 有利于 mdm2 介导的 HDAC3 调节。Mdm2 和 Mdm2/MdmX 的缺失减少了细胞迁移，同时 HDAC3 水平降低。这些数据提供了证据表明，Mdm2 正向调节 HDAC3 的单泛素化和稳定性。
