双酚 A 和己烯雌酚暴露在体外和体内诱导乳腺癌相关长非编码 RNA HOTAIR 的表达。
Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo.
机构信息
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States.
Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, United States.
出版信息
J Steroid Biochem Mol Biol. 2014 May;141:160-70. doi: 10.1016/j.jsbmb.2014.02.002. Epub 2014 Feb 14.
Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES-induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo.
反义转录物，长非编码 RNA HOTAIR 是基因沉默和乳腺癌的关键因子，其转录受到雌二醇的调控。在这里，我们研究了双酚 A (BPA) 和己烯雌酚 (DES) 是否会导致 HOTAIR 表达失调。我们的研究结果表明，BPA 和 DES 可诱导培养的人乳腺癌细胞 (MCF7) 以及大鼠乳腺中的 HOTAIR 表达。荧光素酶检测表明，BPA 和 DES 可诱导 HOTAIR 启动子雌激素反应元件 (EREs)。在存在 BPA 和 DES 的情况下，雌激素受体 (ERs) 和 ER 共调节剂，如 MLL-组蛋白甲基转移酶 (MLL1 和 MLL3)，与 HOTAIR 启动子 EREs 结合，修饰染色质（组蛋白甲基化和乙酰化）并导致基因激活。敲低 ERs 可下调 BPA 和 DES 诱导的 HOTAIR 表达。总之，我们的结果表明，BPA 和 DES 暴露改变了 HOTAIR 启动子的表观遗传编程，导致其在体外和体内的内分泌干扰。
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