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，前列腺异常甲基化的诱导剂几乎是未知的。在这里，我们研究雄激素过量是否可以诱导异常甲基化与否，使用大鼠前列腺癌模型。我们首先确定了两个标记基因，甲基化睾酮/DMAB诱导的浸润性腺癌，除了三个基因以前分离。接下来，我们分析了大鼠背外侧叶甲基化水平的时间分布，发现在睾酮治疗期间诱导了两个基因（Amn 1，Mmp 23）的异常甲基化。雄激素过量并不诱导大鼠前列腺中DNA甲基转移酶的mRNA表达。相反，它诱导前列腺中淋巴细胞和中性粒细胞的浸润。这些结果表明，雄激素过量可诱导前列腺中的异常DNA甲基化，并表明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.