Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer
Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer
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DOI：
10.1038/sj.onc.1208700
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发表时间：
2005-07-28
期刊：
影响因子：
8
通讯作者：
Shridhar, V
中科院分区：
文献类型：
--
作者：
Chien, J;Staub, J;Shridhar, V
表观遗传沉默的CpG的超甲基化代表了一种机制的失活的肿瘤抑制。在这里，我们报告了一个新的候选抑癌基因TCEAL 7在卵巢癌甲基化失活的克隆。TCEAL编码一个1.35 kb的转录本，此前通过cDNA微阵列和抑制性消减cDNA（SSH）分析报告了该转录本在卵巢癌中下调。本报告重点阐述与TCEAL7下调相关的机制。TCEAL 7的表达在大多数卵巢肿瘤和癌细胞系中下调，但以剂量依赖性方式被5-氮杂-2'-脱氧胞苷处理诱导，暗示甲基化是TCEAL 7失活的机制。亚硫酸氢盐修饰的基因组DNA的序列分析，从体细胞杂种与活跃或失活的人类X染色体揭示，TCEAL7是受到X染色体失活。原发性肿瘤和细胞系中TCEAL 7表达的缺失与启动子内CpG位点的甲基化相关。体外CpG位点的甲基化抑制启动子活性，而SmaI位点的选择性去甲基化减弱了这种抑制。最后，TCEAL 7在癌细胞系中的再表达诱导细胞死亡并降低集落形成效率。这些数据表明TCEAL7是一种细胞死亡调节蛋白，在卵巢癌中经常失活，并表明它可能具有肿瘤抑制作用。
Epigenetic silencing by hypermethylation of CpGs represents a mechanism of inactivation of tumor suppressors. Here we report on the cloning of a novel candidate tumor suppressor gene TCEAL7 inactivated by methylation in ovarian cancer. TCEAL codes for a 1.35 kb transcript that was previously reported to be downregulated in ovarian cancer by cDNA microarray and suppression subtraction cDNA (SSH) analyses. This report focuses on the elucidation of mechanisms associated with TCEAL7 downregulation. Expression of TCEAL7 is downregulated in a majority of ovarian tumors and cancer cell lines but induced by 5-aza-2'- deoxycytidine treatment in a dose-dependant manner, implicating methylation as a mechanism of TCEAL7 inactivation. Sequence analyses of bisufite-modified genomic DNA from somatic cell hybrids with either the active or the inactive human X chromosome reveal that TCEAL7 is subjected to X chromosome inactivation. Loss of TCEAL7 expression in primary tumors and cell lines correlates with methylation of a CpG site within the promoter. In vitro methylation of the CpG site suppresses promoter activity whereas selective demethylation of the SmaI site attenuates the suppression. Finally, re-expression of TCEAL7 in cancer cell lines induces cell death and reduces colony formation effciency. These data implicate TCEAL7 as a cell death regulatory protein that is frequently inactivated in ovarian cancers and suggest that it may function as a tumor suppressor.