State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
Oncol Rep. 2014 Jan;31(1):34-40. doi: 10.3892/or.2013.2810. Epub 2013 Oct 24.
Androgen receptor (AR) plays a critical role during the development and progression of prostate cancer in which microRNA miR-375 is overexpressed and correlated with tumor progression. Although DNA methylation is a key mechanism for the repression of gene expression, the relationship between AR and the expression or the hypermethylation of miR-375 is unknown. In this study, we found that AR-positive prostate cancer (PCa) cells showed high expression levels and hypomethylation of the miR-375. In contrast, AR-negative PCa cells displayed low levels and hypermethylation of the miR-375. Addition of 5-Aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, into the culture medium reversed the low expression levels of miR-375 in the AR negative PCa cells. In addition, the total activity levels of DNA methyltransferases (DNMTs) were high in AR-negative PCa cells, in which hypermethylation of miR-375 promoter and low expression levels of miR-375 were observed. Taken together, these findings indicate that the negative correlation between AR and total DNMT activity is one of mechanisms to influence the methylation status of miR-375 promoter, which in turn regulates the expression of miR-375.
雄激素受体 (AR) 在前列腺癌的发展和进展中起着关键作用，其中 microRNA miR-375 过表达并与肿瘤进展相关。尽管 DNA 甲基化是抑制基因表达的关键机制，但 AR 与 miR-375 的表达或高甲基化之间的关系尚不清楚。在这项研究中，我们发现 AR 阳性前列腺癌 (PCa) 细胞表现出 miR-375 的高表达水平和低甲基化。相比之下，AR 阴性 PCa 细胞显示出 miR-375 的低水平和高甲基化。在培养基中添加 5-Aza-2'-脱氧胞苷，一种 DNA 甲基化的特异性抑制剂，可逆转 AR 阴性 PCa 细胞中 miR-375 的低表达水平。此外，AR 阴性 PCa 细胞中的总 DNA 甲基转移酶 (DNMT) 活性水平较高，观察到 miR-375 启动子的高甲基化和 miR-375 的低表达水平。综上所述，这些发现表明 AR 与总 DNMT 活性之间的负相关是影响 miR-375 启动子甲基化状态的机制之一，进而调节 miR-375 的表达。
