Promoter CpG hypermethylation and downregulation of DICE1 expression in prostate cancer
Promoter CpG hypermethylation and downregulation of DICE1 expression in prostate cancer
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DOI：
10.1038/sj.onc.1208824
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发表时间：
2005-10-06
期刊：
影响因子：
8
通讯作者：
Wieacker, PF
中科院分区：
文献类型：
--
作者：
Röpke, A;Buhtz, P;Wieacker, PF
人类染色体13q14杂合性缺失的一个关键区域包含肿瘤抑制基因DICE1 （DDX26）。为了阐明肿瘤细胞中DICE1表达降低的原因，我们分析了DICE1基因上游的启动子序列。该序列GC含量高，含有丰富的CpG位点和转录因子结合位点。在DICE1基因上游800bp序列的三个重叠片段中鉴定出启动子活性。在DICE1启动子区域检测到一个13 bp的缺失多态性，与未缺失的变体相比，其活性降低。然而，在男性对照样本和前列腺癌或良性前列腺增生患者中，这种13bp的缺失率相似。前列腺癌细胞DU145和LNCaP中DICE1表达降低。这种下调与DICE1启动子的高甲基化有关。用5-氮杂胞苷治疗两种前列腺癌细胞系可导致DICE1表达上调。在分析的8例前列腺癌中，有4例观察到DICE1启动子CpG位点的高甲基化。本研究提示前列腺癌细胞中DICE1的转录抑制是由DICE1启动子区域的高甲基化引起的。
A critical region of loss of heterozygosity on human chromosome 13q14 harbors the tumor suppressor gene DICE1 (DDX26). To elucidate the reduced DICE1 expression in tumor cells, the putative promoter sequence upstream of the DICE1 gene was analysed. This sequence shows a high GC content and is rich in CpG sites and binding sites of transcriptional factors. Promoter activity was identified within three overlapping fragments of the 800 bp sequence upstream of the DICE1 gene. A 13 bp deletion polymorphism detected in the DICE1 promoter region showed a decreased activity compared with the undeleted variant. However, this 13 bp deletion was seen in male control samples and patients with prostate cancer or benign prostatic hyperplasia at similar rates. A reduced DICE1 expression was observed in prostate cancer cell lines DU145 and LNCaP. This downregulation is associated with hypermethylation of the DICE1 promoter. Treatment of both prostate cancer cell lines with 5-azacytidine leads to upregulation of DICE1 expression. Hypermethylation of CpG sites of the DICE1 promoter was observed in four of eight analysed prostate cancers. This study suggests that transcriptional repression of DICE1 is caused by hypermethylation of the DICE1 promoter region in prostate cancer cells.