Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis.
Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis.
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DOI：
10.1158/1541-7786.mcr-11-0605
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Walker CL
中科院分区：
文献类型：
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作者：
Greathouse KL;Bredfeldt T;Everitt JI;Lin K;Berry T;Kannan K;Mittelstadt ML;Ho SM;Walker CL
在发育的敏感窗口期暴露于环境中可以重新编程正常的生理反应，并在生命后期改变疾病易感性，这一过程称为发育重编程。例如，在生殖道发育过程中暴露于异种雌激素己烯雌酚（DES）可以重新编程子宫肌层中的雌激素反应基因表达，导致成年子宫对激素的高反应性和促进子宫内膜依赖性子宫平滑肌瘤。我们在这里表明，环境雌激素染料木黄酮（GEN），大豆植物雌激素，和增塑剂双酚A（BPA），不同的发展模式的重编程和促进子宫肿瘤（平滑肌瘤）。虽然GEN和BPA都诱导发育中子宫的基因组雌激素受体（ER）信号传导，但只有GEN诱导PI 3 K/AKT非基因组ER信号传导至组蛋白甲基转移酶增强子Zeste同源物2（EZH 2）。因此，这种“前基因组”信号传导磷酸化并抑制EZH 2，并降低染色质中H3 K27抑制标记的水平。此外，只有GEN导致成年子宫肌层中的雌激素反应基因对激素反应过度;在BPA暴露的子宫中，雌激素反应基因受到抑制。重要的是，EZH 2参与减少与增加H3 K27甲基化的这种模式与这些异种雌激素对肿瘤发生的影响相关。GEN的发育重编程促进了子宫平滑肌瘤的发展，增加了肿瘤的发病率和多样性，而BPA没有。这些数据表明，环境雌激素在发育中的子宫中具有独特的非基因组效应，这决定了它们参与表观遗传调节因子EZH 2的能力，在发育重编程期间降低染色质中抑制性表观遗传组蛋白H3 K27甲基标记的水平，并促进子宫肿瘤发生。
Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol (DES) during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyper-responsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein (GEN), a soy phytoestrogen, and the plasticizer bisphenol A (BPA), differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. While both GEN and BPA induce genomic estrogen receptor (ER) signaling in the developing uterus, only GEN induced PI3K/AKT non-genomic ER signaling to the histone methyltransferase Enhancer of Zeste homolog 2 (EZH2). As a result, this “pre-genomic” signaling phosphorylates and represses EZH2, and reduces levels of H3K27 repressive mark in chromatin. Furthermore, only GEN caused estrogen-responsive genes in the adult myometrium to become hyper-responsive to hormone; estrogen-responsive genes were repressed in BPA exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by GEN promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, while BPA did not. These data demonstrate that environmental estrogens have distinct non-genomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis.