Silencing of the UCHL1 gene in human colorectal and ovarian cancers
Silencing of the UCHL1 gene in human colorectal and ovarian cancers
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DOI：
10.1002/ijc.22025
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发表时间：
2006-09-15
影响因子：
6.4
通讯作者：
Ushijima, Toshikazu
中科院分区：
文献类型：
--
作者：
Okochi-Takada, Eriko;Nakazawa, Kazuyuki;Ushijima, Toshikazu
异常的DNA甲基化与许多类型的人类癌症有关。为了鉴定在人结肠直肠癌中沉默的基因，我们对通过用去甲基化剂5-氮杂-2 '-脱氧胞苷（5-aza-dC）处理HCT 116人结肠癌细胞诱导表达的基因进行了微阵列分析。7个已知基因被鉴定为上调（>= 8倍），表达水平是平均水平的两倍以上。其中包括UCHL 1基因（也称为PGP9.5），它参与调节细胞泛素水平。在HCT 116细胞中，其启动子区的一个密集的CpG岛完全甲基化，未检测到mRNA。5-Aza-dC处理HCT 116细胞可诱导CpG岛的剂量依赖性去甲基化，并恢复UCHL 1 mRNA和蛋白表达。在12个人结直肠癌细胞系中的11个中观察到UCHL 1沉默，并且在17个原发性结直肠癌中的8个中检测到其甲基化。此外，在13个卵巢癌细胞系中的6个中观察到UCHL 1沉默，并且在17个原发性卵巢癌中的1个中检测到其甲基化。这些结果表明，UCHL 1在人类结直肠癌和卵巢癌中通过其启动子甲基化而失活，并表明存在细胞泛素水平的干扰。(c)2006 Wiley-Liss，Inc.
Aberrant DNA methylation is associated with many types of human cancers. To identify genes silenced in human colorectal cancers, we performed a microarray analysis for genes whose expression was induced by treatment of HCT116 human colon cancer cells with a demethylating agent, 5-aza-2'-deoxvcitidine (5-aza-dC). Seven known genes were identified as being upregulated (>= 8-fold) and expressed at more than twice as high as the average level. Among these was the UCHL1 gene (also known as PGP9.5), which is involved in regulation of cellular ubiquitin levels. A dense CpG island in its promoter region was completely methylated in HCT116 cells, and no mRNA was detected. 5-Aza-dC treatment of HCT116 cells induced dose-dependent demethylation of the CpG island, and restored UCHL1 mRNA and protein expression. UCHL1 silencing was observed in 11 of 12 human colorectal cancer cell lines, and its methylation was detected in 8 of 17 primary colorectal cancers. Further, UCHL1 silencing was observed in 6 of 13 ovarian cancer cell lines, and its methylation was detected in 1 of 17 primary ovarian cancers. These results showed that UCHL1 is inactivated in human colorectal and ovarian cancers by its promoter methylation, and suggest that disturbance of cellular ubiquitin levels is present. (c) 2006 Wiley-Liss, Inc.