Peng Yu-Ting, Wu Wen-Ren, Chen Lih-Ren, Kuo Kung-Kai, Tsai Cheng-Hui, Huang Yu-Ting, Lan Yu-Hsuan, Chang Fang-Rong, Wu Yang-Chang, Shiue Yow-Ling
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
Division of Physiology, Livestock Research Institute, Council of Agriculture, Executive Yuan, Taiwan.
Toxicol Rep. 2015 Jan 25;2:322-332. doi: 10.1016/j.toxrep.2015.01.010. eCollection 2015.
Cell cycle deregulation is common in human hepatocellular carcinoma (HCC). To ensure proper cell cycle controlling, cyclin/cyclin-dependent kinases (CDK) complexes are tightly regulated by CDK inhibitors (CKIs) in normal cells. However, insufficient cyclin-dependent kinase inhibitor 1B (CDKN1B, also known as p27) and CDKN1C (p57) proteins are characteristics of high-risk HCC. In two HCC-derived cell lines with distinct genetic backgrounds, we identified a small natural compound, goniothalamin (GTN), serving as an inducer of CKIs. In TP53-mutated (Y220C) and retinoblastoma 1 (RB1)-positive Huh-7 cells, GTN stabilized CDKN1B protein levels by targeting the degradation of its specific E3 ubiquitin ligase (S-phase kinase-associated protein 2). Alternatively, in TP53- and RB1-negative Hep-3B cells, GTN increased transcription and its subsequent translation by acting as a histone deacetylase inhibitor. In both cell lines, GTN induced G/G cell cycle arrest, delayed S phase entry of cells and inhibited anchorage-independent cell growth which might be attributed to the upregulation of CKIs and downregulation of several positive cell cycle regulators, including CDC28 protein kinase regulator subunit 1B, cyclin E1 and D1, cyclin-dependent kinase 2 (CDK2), CDK4, CDK6, E2F transcription factor 1 and/or transcription factor Dp-1. Therefore, GTN might represent a novel class of anticancer drug that induces CKIs through post-translational and epigenetic modifications.
细胞周期失调在人类肝细胞癌（HCC）中很常见。为确保细胞周期的正常调控，在正常细胞中，细胞周期蛋白/细胞周期蛋白依赖性激酶（CDK）复合物受到CDK抑制剂（CKIs）的严格调控。然而，细胞周期蛋白依赖性激酶抑制剂1B（CDKN1B，也称为p27）和CDKN1C（p57）蛋白不足是高危HCC的特征。在两个具有不同遗传背景的HCC衍生细胞系中，我们鉴定出一种小的天然化合物——角鲨胺（GTN），它可作为CKIs的诱导剂。在TP53突变（Y220C）且视网膜母细胞瘤1（RB1）阳性的Huh-7细胞中，GTN通过靶向其特异性E3泛素连接酶（S期激酶相关蛋白2）的降解来稳定CDKN1B蛋白水平。另外，在TP53和RB1阴性的Hep-3B细胞中，GTN作为组蛋白脱乙酰酶抑制剂发挥作用，增加转录及其后续翻译。在这两种细胞系中，GTN均诱导G / G细胞周期停滞，延迟细胞进入S期，并抑制不依赖贴壁的细胞生长，这可能归因于CKIs的上调和几种细胞周期正向调节因子的下调，包括细胞周期蛋白依赖性激酶调节亚基1B、细胞周期蛋白E1和D1、细胞周期蛋白依赖性激酶2（CDK2）、CDK4、CDK6、E2F转录因子1和/或转录因子Dp-1。因此，GTN可能代表一类新型抗癌药物，可通过翻译后修饰和表观遗传修饰诱导CKIs。
