Molecular mechanisms for induction of DNA methylation by testosterone overdose in the rat prostate

DNA甲基化异常与前列腺癌的发生密切相关。然而，前列腺中异常甲基化的诱导者几乎是未知的。在这里，我们使用了一个大鼠前列腺癌模型，研究了雄激素过量是否可以诱导异常甲基化。除了先前分离的三个基因外，我们还首次鉴定了两个标记基因，在睾丸激素/DMAB诱导的侵袭性腺癌中发生甲基化。接下来，我们分析了大鼠背外侧叶甲基化水平的时间分布，发现在睾酮处理期间，两个基因(Amn1，Mmp23)的异常甲基化被诱导。雄激素过量不能诱导大鼠DNA甲基转移酶基因的表达。相反，它诱导了淋巴细胞和中性粒细胞在前列腺中的渗透。这些结果表明，雄激素过量可以诱导前列腺中异常的DNA甲基化，并提示炎症反应是异常甲基化诱导的基础。

Aberrant DNA methylation is deeply involved in prostate carcinogenesis. However, inducers of aberrant methylation in the prostate are almost unknown. Here, we investigated whether androgen excess can induce aberrant methylation or not, using a rat prostate cancer model. We first identified two marker genes, methylated in testosterone/DMAB-induced invasive adenocarcinomas, in addition to three genes previously isolated. Next, we analyzed temporal profiles of methylation levels in the dorsolateral lobe of rats, and found that aberrant methylation of two genes (Amn1, Mmp23) was induced during the testosterone treatment. Androgen excess did not induce mRNA expression of DNA methyltransferases in the rat prostrate. In contrast, it induced infiltration of lymphocytes and neutrophils in the prostate. These results demonstrated that androgen excess can induce aberrant DNA methylation in the prostate, and suggested that inflammatory response underlies aberrant methylation induction.