Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors
Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors
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DOI：
10.1208/s12248-013-9493-3
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发表时间：
2013-07-01
期刊：
影响因子：
4.5
通讯作者：
Kong, Ah-Ng Tony
中科院分区：
文献类型：
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作者：
Wu, Tien-Yuan;Khor, Tin Oo;Kong, Ah-Ng Tony
3，3 '-二吲哚基甲烷（DIM）目前正在许多临床试验中进行研究，包括前列腺癌、乳腺癌和宫颈癌，并已在几种体内和体外模型中显示具有抗癌作用。此前，DIM已被报道在TRAMP小鼠前列腺癌发生中具有癌症化学预防作用;然而，体内机制尚不清楚。本研究旨在研究DIM在TRAMP-C1细胞和TRAMP小鼠模型中的体外和体内表观遗传学调节。利用TRAMP-C1细胞的体外研究表明，DIM抑制DNMT表达并逆转Nrf 2的CpG甲基化状态，导致Nrf 2和Nrf 2靶基因NQO 1的表达增强。体内研究显示，喂食补充DIM的饮食的TRAMP小鼠的肿瘤发生和转移发生率比未治疗的对照组低得多，与之前报道的相似。在前列腺组织中，DIM增加了细胞凋亡，降低了细胞增殖，并增强了Nrf 2和Nrf 2靶基因NQO 1的表达。重要的是，免疫组织化学分析表明，DIM减少了整体CpG 5-甲基胞嘧啶甲基化。针对早期癌症化学预防靶基因之一Nrf 2，亚硫酸氢盐基因组测序显示，DIM降低了Nrf 2启动子区域前5个CpG的甲基化状态，这与体外TRAMP-C1细胞的结果一致。总之，我们目前的研究表明，DIM是一种有效的前列腺癌化学预防剂，包括Nrf 2在内的CpG表观遗传修饰可能是DIM发挥其化学预防作用的潜在机制。
3,3'-diindolylmethane (DIM) is currently being investigated in many clinical trials including prostate, breast, and cervical cancers and has been shown to possess anticancer effects in several in vivo and in vitro models. Previously, DIM has been reported to possess cancer chemopreventive effects in prostate carcinogenesis in TRAMP mice; however, the in vivo mechanism is unclear. The present study aims to investigate the in vitro and in vivo epigenetics modulation of DIM in TRAMP-C1 cells and in TRAMP mouse model. In vitro study utilizing TRAMP-C1 cells showed that DIM suppressed DNMT expression and reversed CpG methylation status of Nrf2 resulting in enhanced expression of Nrf2 and Nrf2-target gene NQO1. In vivo study, TRAMP mice fed with DIM-supplemented diet showed much lower incidence of tumorigenesis and metastasis than the untreated control group similar to what was reported previously. DIM increased apoptosis, decreased cell proliferation and enhanced Nrf2 and Nrf2-target gene NQO1 expression in prostate tissues. Importantly, immunohistochemical analysis showed that DIM reduced the global CpG 5-methylcytosine methylation. Focusing on one of the early cancer chemopreventive target gene Nrf2, bisulfite genomic sequencing showed that DIM decreased the methylation status of the first five CpGs of the Nrf2 promoter region, corroborating with the results of in vitro TRAMP-C1 cells. In summary, our current study shows that DIM is a potent cancer chemopreventive agent for prostate cancer and epigenetic modifications of the CpG including Nrf2 could be a potential mechanism by which DIM exerts its chemopreventive effects.