Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells.
Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells.
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DOI：
10.1158/0008-5472.can-08-4914
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Huang TH
中科院分区：
文献类型：
--
作者：
Hsu PY;Deatherage DE;Rodriguez BA;Liyanarachchi S;Weng YI;Zuo T;Liu J;Cheng AS;Huang TH
早期暴露于异种雌激素可能会使成年后患乳腺癌的风险增加。可能的是，随着时间的推移，长寿的自我再生的上皮祖细胞更容易受到这些暴露损伤，并通过表观遗传机制将损伤的记忆传递给它们分化的后代。在这里，我们使用含有祖细胞的乳腺球作为体外暴露模型来研究这种表观遗传效应。表达谱分析表明，相对于对照细胞，9.1%的microRNA（898个位点中的82个）在暴露于合成雌激素己烯雌酚的乳腺球衍生的上皮后代中发生了改变。抑制性染色质标记，组蛋白H3的三甲基赖氨酸27（H3 K27 me 3）和组蛋白H3的二甲基赖氨酸9（H3 K9 me 2），被发现在下调的位点，miR-9-3，在上皮细胞预先暴露于己烯雌酚。这是伴随着招聘的DNA甲基转移酶1，导致异常增加的DNA甲基化的启动子CpG岛在乳腺球衍生的上皮细胞上的己烯雌酚预暴露。功能分析表明，miR-9-3在p53相关的凋亡途径中发挥作用。因此，这种基因的表观遗传沉默降低了这种细胞功能，促进了乳腺癌细胞的增殖。这种microRNA的启动子超甲基化可能是早期乳腺癌发展的标志，通过表观遗传和基于microRNA的疗法恢复其表达是未来治疗这种疾病的另一种可行选择。
Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1% of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease.