Second Department of Pathology, Kansai Medical University, Moriguchi-shi, Osaka 570-8506, Japan.
Oncol Rep. 2012 Jul;28(1):105-10. doi: 10.3892/or.2012.1758. Epub 2012 Apr 6.
Vorinostat is a histone deacetylase inhibitor that blocks cancer cell proliferation through the regulation of cyclin-dependent kinase inhibitors. We, herein, examined the involvement of S-phase kinase-associated protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1), the components of the SCFSkp2-Cks1 (Skp1/Cul1/F-box protein) ubiquitin ligase complex, in the regulation of p27 and p21 during vorinostat-induced growth arrest of MDA-MB-231 and MCF-7 human breast cancer cells. Vorinostat significantly reduced BrdU incorporation in MDA-MB-231 and MCF-7 cells, which was associated with increased p27 and p21 protein levels without concomitant induction of p27 mRNA. Vorinostat-induced accumulation of p27 and p21 proteins was inversely correlated with the mRNA and protein levels of Skp2 and Cks1. Cycloheximide chase analysis revealed that vorinostat increased the half-life of p27 and p21 proteins. The accumulation of p27 and p21 proteins was attenuated by forced expression of Skp2 and Cks1, which conferred resistance to the vorinostat-induced S-phase reduction. These results suggest that vorinostat-induced growth arrest may be in part due to the enhanced protein stability of p27 and p21 through the downregulation of Skp2 and Cks1.
伏立诺他是一种组蛋白去乙酰化酶抑制剂，通过调节细胞周期蛋白依赖性激酶抑制剂来阻止癌细胞增殖。在此，我们研究了 S 期激酶相关蛋白 2（Skp2）和细胞周期蛋白依赖性激酶亚基 1（Cks1）在伏立诺他诱导的 MDA-MB-231 和 MCF-7 人乳腺癌细胞生长抑制过程中对 p27 和 p21 的调节作用。伏立诺他显著降低了 MDA-MB-231 和 MCF-7 细胞中 BrdU 的掺入，这与 p27 和 p21 蛋白水平的增加相关，而 p27 mRNA 没有同时诱导。伏立诺他诱导的 p27 和 p21 蛋白积累与 Skp2 和 Cks1 的 mRNA 和蛋白水平呈负相关。环己酰亚胺追踪分析表明，伏立诺他增加了 p27 和 p21 蛋白的半衰期。Skp2 和 Cks1 的强制表达减弱了 p27 和 p21 蛋白的积累，这赋予了对伏立诺他诱导的 S 期减少的抗性。这些结果表明，伏立诺他诱导的生长抑制可能部分归因于 Skp2 和 Cks1 的下调导致 p27 和 p21 蛋白稳定性增强。
