Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation
Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation
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DOI：
10.1038/sj.onc.1209154
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发表时间：
2006-02-01
期刊：
影响因子：
8
通讯作者：
Tao, Q
中科院分区：
文献类型：
--
作者：
Ying, J;Li, H;Tao, Q
原钙粘蛋白是细胞粘附分子钙粘蛋白超家族中最大的一个亚类。它们的主要功能知之甚少，尽管有些与神经系统发育有关。由于肿瘤特异性启动子甲基化是肿瘤抑制基因（tumor suppressor genes，TSG）的标志，我们采用甲基化消减结合药物去甲基化的方法寻找表观遗传学失活的TSG，并鉴定了鼻咽癌（nasopharyngeal carcinoma，NPC）中PCDH 10 CpG岛的甲基化序列。PCDH 10在所有正常成人和胎儿组织中广泛表达，包括上皮细胞，但表达水平不同。它位于4q28.3-一个区域与半合子缺失检测阵列CGH在NPC细胞系，然而，PCDH 10本身并不位于缺失。相反，它的转录沉默和启动子甲基化频繁地以双等位基因方式在多种癌细胞系中检测到，包括12/12的鼻咽癌、13/16的食管癌、3/4的乳腺癌、5/5的结直肠癌、3/4的宫颈癌、2/5的肺癌和2/8的肝细胞癌细胞系，但在任何永生化的正常上皮细胞系中均未检测到。异常甲基化在多原发癌中更常见（NPC为82%，其他癌为42-51%），而在正常组织中则不常见。PCDH 10的转录沉默可以通过5-氮杂-2 '-脱氧胞苷的药物去甲基化或DNMT 1和DNMT 3B双敲除的遗传去甲基化来逆转，表明直接的表观遗传机制。PCDH 10的异位表达强烈抑制肿瘤细胞的生长、迁移、侵袭和集落形成。虽然几种经典的钙粘蛋白作为TSG的表观遗传和遗传破坏在肿瘤中已有很好的记录，但这是第一次报道广泛表达的原钙粘蛋白也可以作为TSG，其在多种癌中经常表观遗传失活。
Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumorspecific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3-a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2'-deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.