Stage-specific alterations of DNA methyltransferase expression, DNA hypermethylation, and DNA hypomethylation during prostate cancer progression in the transgenic adenocarcinoma of mouse prostate model.
Stage-specific alterations of DNA methyltransferase expression, DNA hypermethylation, and DNA hypomethylation during prostate cancer progression in the transgenic adenocarcinoma of mouse prostate model.
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DOI：
10.1158/1541-7786.mcr-08-0040
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发表时间：
2008-08
期刊：
影响因子：
--
通讯作者：
Karpf AR
中科院分区：
文献类型：
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作者：
Morey Kinney SR;Smiraglia DJ;James SR;Moser MT;Foster BA;Karpf AR
我们在转基因小鼠前列腺腺癌（TRAMP）模型中分析了前列腺癌进展期的DNA甲基转移酶蛋白表达和DNA甲基化模式，包括前列腺上皮内瘤变（PIN）、高分化肿瘤（WD）、早期低分化肿瘤（EPD）和晚期低分化肿瘤（LPD）。Dnmt1、Dnmt3a和Dnmt3b蛋白的表达在所有阶段都增加，然而，在将Dnmt蛋白归一化到Cyclin A以解释细胞周期调节后，Dnmt蛋白在PIN和WD中仍然过表达，但在低分化肿瘤中没有过表达。限制性里程碑基因组扫描（RLGS）对位点特异性甲基化的分析显示，高甲基化发生率仅在低分化（EPD和LPD）肿瘤中存在。RLGS鉴定的几个基因显示与mRNA过表达相关的下游区域超甲基化，包括p16INK4a、p19ARF和Cacna1a。平行基因表达和DNA甲基化分析表明，在前列腺肿瘤进展过程中，基因过表达先于下游超甲基化。与基因高甲基化相反，基因组DNA低甲基化，包括重复元件的低甲基化和基因组5mdC的丢失，发生在前列腺癌的早期和晚期。DNA高甲基化和DNA低甲基化在TRAMP中不相关，Dnmt蛋白表达与这两个参数都不相关，除了Dnmt1表达与DNA高甲基化之间存在临界显著关联。总之，我们的数据揭示了体内模型系统中前列腺肿瘤进展过程中DNA甲基化途径关键改变的相对时间和关系。
We analyzed DNA methyltransferase protein expression and DNA methylation patterns during four progressive stages of prostate cancer in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model, including prostatic intraepithelial neoplasia (PIN), well differentiated tumors (WD), early poorly differentiated tumors (EPD), and late poorly differentiated tumors (LPD). Dnmt1, Dnmt3a, and Dnmt3b protein expression are increased in all stages, however, after normalization to Cyclin A to account for cell cycle regulation, Dnmt proteins remained over-expressed in PIN and WD, but not in poorly differentiated tumors. Restriction Landmark Genomic Scanning (RLGS) analysis of locus-specific methylation revealed a high incidence of hypermethylation only in poorly differentiated (EPD and LPD) tumors. Several genes identified by RLGS showed hypermethylation of downstream regions correlating with mRNA overexpression, including p16INK4a, p19ARF, and Cacna1a. Parallel gene expression and DNA methylation analyses suggests that gene overexpression precedes downstream hypermethylation during prostate tumor progression. In contrast to gene hypermethylation, genomic DNA hypomethylation, including hypomethylation of repetitive elements and loss of genomic 5mdC, occurred in both early and late stages of prostate cancer. DNA hypermethylation and DNA hypomethylation did not correlate in TRAMP, and Dnmt protein expression did not correlate with either parameter, with the exception of a borderline significant association between Dnmt1 expression and DNA hypermethylation. In summary, our data reveal the relative timing of and relationship between key alterations of the DNA methylation pathway occurring during prostate tumor progression in an in vivo model system.