Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer
Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer
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DOI：
10.1002/ijc.20971
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发表时间：
2005-07-10
影响因子：
6.4
通讯作者：
Wake, N
中科院分区：
文献类型：
--
作者：
Kamikihara, T;Arima, T;Wake, N
ZAC是位于染色体6 q24上的父系表达的印记基因，在已知含有几种类型的肿瘤（包括人卵巢癌（HOC））的肿瘤抑制基因的区域内。我们未能在肿瘤材料中鉴定ZAC基因的基因突变。许多印迹基因含有差异等位基因特异性甲基化区域（DMR），并具有受DNA甲基化调控的启动子活性。异常的DNA甲基化是肿瘤形成的常见特征，在一些HOC病例中已经报道了ZAC基因座的DNA甲基化变化。我们研究了DNA甲基化和ZAC mRNA表达水平在一个较大的样本的主要HOC材料，获得激光捕获显微切割。在大多数样品中ZAC mRNA表达降低，这与ZAC-DMR的高甲基化相关。用去甲基化剂处理高甲基化细胞系恢复ZAC表达。我们的研究表明，ZAC的转录沉默可能是由HOC中的DNA甲基化引起的。ZAC的强制表达导致增殖的减少和凋亡细胞死亡的显著诱导。ZAC介导的细胞凋亡信号是p53非依赖性的，并通过半胱天冬酶3、8和9的抑制剂消除。因此，ZAC的表达降低将有利于肿瘤进展。由于局部和晚期肿瘤之间的DNA甲基化或ZAC mRNA表达没有显著差异，我们的数据表明ZAC的丢失是HOC中相对早期的事件。（本文的补充材料可在国际癌症杂志网站http://www.interscience.wiley.com/jpages/0020-7136/ suppmat/index.html上找到。(c)2005 Wiley-Liss，Inc.
ZAC is a paternally expressed, imprinted gene located on chromosome 6q24, within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer (HOC). We have failed to identify genetic mutations in the ZAC gene in tumor material. Many imprinted genes contain differentially allele-specific-methylated regions (DMR) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by laser capture microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3, 8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/ suppmat/index.html.) (c) 2005 Wiley-Liss, Inc.