The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer
The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer
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DOI：
10.1002/ijc.27628
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发表时间：
2012-09-15
影响因子：
6.4
通讯作者：
Schulz, Wolfgang A.
中科院分区：
文献类型：
--
作者：
Kloth, Michael;Goering, Wolfgang;Schulz, Wolfgang A.
表观遗传畸变在前列腺癌中很常见，可能有助于检测和鉴别。然而，这些变化的基本机制和顺序仍有待充分阐明。肿瘤抑制基因RARRES 1（TIG1）在几种癌症中经常高甲基化。在注意到其旁系同源的邻居基因LXN在3q25.32的表达变化后，我们使用焦磷酸测序来定量这两个基因的DNA甲基化，并确定其与86例根治性前列腺癌组织中临床病理参数的关系。LXN和RARRES 1的甲基化高度相关。增加甲基化与更差的临床特征相关，包括生化复发和两种基因表达降低。然而，三个相邻基因的表达不受影响。有趣的是，RARRES 1甲基化受到其启动子中rs6441224单核苷酸多态性（SNP）基因型的影响。我们发现该SNP位于ETS家族反应元件内，并且在报告基因测定中，更强烈的甲基化等位基因赋予较低的活性。在前列腺癌细胞系中也检测到癌组织中RARRES 1和LXN的伴随甲基化，并显示与抑制性组蛋白修饰和转录下调相关。总之，我们发现ETS家族靶基因RARRES1的基因型相关超甲基化影响其邻近基因LXN的甲基化，并可用作预后生物标志物。
Epigenetic aberrations are frequent in prostate cancer and could be useful for detection and prognostication. However, the underlying mechanisms and the sequence of these changes remain to be fully elucidated. The tumor suppressor gene RARRES1 (TIG1) is frequently hypermethylated in several cancers. Having noted changes in the expression of its paralogous neighbor gene LXN at 3q25.32, we used pyrosequencing to quantify DNA methylation at both genes and determine its relationship with clinicopathological parameters in 86 prostate cancer tissues from radical prostatectomies. Methylation at LXN and RARRES1 was highly correlated. Increasing methylation was associated with worse clinical features, including biochemical recurrence, and decreased expression of both genes. However, expression of three neighboring genes was unaffected. Intriguingly, RARRES1 methylation was influenced by the genotype of the rs6441224 single-nucleotide polymorphism (SNP) in its promoter. We found that this SNP is located within an ETS-family-response element and that the more strongly methylated allele confers lower activity in reporter assays. Concomitant methylation of RARRES1 and LXN in cancerous tissues was also detected in prostate cancer cell lines and was shown to be associated with repressive histone modifications and transcriptional downregulation. In conclusion, we found that genotype-associated hypermethylation of the ETS-family target gene RARRES1 influences methylation at its neighbor gene LXN and could be useful as a prognostic biomarker.