Chemopreventive agent 3,3'-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases.
Chemopreventive agent 3,3'-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases.
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DOI：
10.1158/0008-5472.can-09-1924
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Guo B
中科院分区：
文献类型：
--
作者：
Li Y;Li X;Guo B
3,3'-二吲哚甲烷 (DIM) 是一种抗癌剂，可通过未知机制诱导细胞周期停滞和细胞凋亡。在此，我们报道 DIM 在结肠癌细胞中选择性诱导蛋白酶体介导的 I 类组蛋白脱乙酰酶（HDAC1、HDAC2、HDAC3 和 HDAC8）降解，而不影响 II 类 HDAC 蛋白。在体内裸鼠肿瘤异种移植物中也观察到 DIM 诱导的 I 类 HDAC 下调。 DIM 处理导致 HDAC 耗竭，导致 CDKN1A/WAF1/CIP1 和 CDKN1B/KIP1 基因（分别编码细胞周期蛋白依赖性激酶抑制剂 p21 和 p27）启动子上的 HDAC 活性降低，并显着增加 p21 和 p27 的表达，从而使细胞停滞在细胞周期的 G2 期。 HDAC 的降解也会导致 DNA 损伤并引发细胞凋亡。因此，DIM 通过选择性地靶向 I 类 HDAC 来促进其降解。
3,3′-Diindolylmethane (DIM) is an anti-cancer agent that induces cell cycle arrest and apoptosis through unknown mechanisms. Here, we report that DIM selectively induced proteasome-mediated degradation of the class I histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC8) in colon cancer cells, without affecting the class II HDAC proteins. DIM-induced down-regulation of the class I HDACs was also observed in vivo in tumor xenografts in nude mice. The depletion of the HDACs as the result of DIM treatment caused a reduction of the HDAC activity on the promoters of CDKN1A/WAF1/CIP1 and CDKN1B/KIP1 genes (encoding cyclin-dependent kinase inhibitors p21 and p27, respectively) and significantly increased the expression of p21 and p27, which arrested cells at the G2 phase of the cell cycle. The degradation of the HDACs also caused DNA damage and triggered apoptosis. Thus, DIM acts by selectively targeting the class I HDACs to promote their degradation.