Section of Genetics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
Genes Chromosomes Cancer. 2010 May;49(5):480-6. doi: 10.1002/gcc.20758.
ZAC/PLAGL1 is a ubiquitously expressed, imprinted tumor suppressor gene located on 6q24, a chromosomal region that is frequently deleted in diffuse large B-cell lymphoma (DLBCL). Like p53, ZAC regulates cell cycle arrest and apoptosis concomitantly, and loss of expression is implicated in tumorigenesis in a variety of different cancers. In most tissues, ZAC transcription is monoallelic and driven by the paternal allele of promoter P1, which lies within a differentially methylated CpG island (DMR). In human blood cells, ZAC transcription is driven by promoter P2, which lies within an unmethylated CpG island and produces biallelic transcripts. Previous reports of epigenetic changes of ZAC in tumors have focused on P1, showing frequent loss of expression caused by paternal allele hypermethylation or loss of heterozygosity (LOH). As ZAC expression in normal B lymphocytes is derived from P2, in DLBCL we analyzed both promoters for gene expression, LOH and abnormal methylation. Loss of P2 transcription was observed in 8 of 11 lymphomas (73%), even though the P2 CpG island remained unmethylated. Three lymphomas showed evidence of LOH (23%), and abnormal methylation of the P1 DMR was observed in an additional four (31%), despite minimal P1 activity in normal B lymphocytes. These data indicate that downregulation of ZAC occurs in DLBCL, as in other cancers. However, unlike P1, transcriptional repression of P2 is not caused by hypermethylation of its associated CpG island in tumors. The mechanistic relationship between altered ZAC expression and epigenetic changes at its promoters thus appears more complex than previously supposed.
ZAC/PLAGL1 是一个广泛表达的印记肿瘤抑制基因，位于 6q24 染色体区域，该区域在弥漫性大 B 细胞淋巴瘤（DLBCL）中经常缺失。与 p53 一样，ZAC 同时调节细胞周期停滞和细胞凋亡，表达缺失与多种不同癌症的肿瘤发生有关。在大多数组织中，ZAC 转录是单等位基因的，由位于差异甲基化 CpG 岛（DMR）内的父本等位基因 P1 启动子驱动。在人类血细胞中，ZAC 转录由位于未甲基化 CpG 岛内的启动子 P2 驱动，并产生双等位基因转录本。先前关于肿瘤中 ZAC 的表观遗传变化的报道主要集中在 P1 上，显示出由于父本等位基因过度甲基化或杂合性丢失（LOH）导致的表达频繁丧失。由于正常 B 淋巴细胞中的 ZAC 表达源自 P2，因此在 DLBCL 中，我们分析了两个启动子的基因表达、LOH 和异常甲基化。即使 P2CpG 岛保持未甲基化，也观察到 11 个淋巴瘤中的 8 个（73%）失去 P2 转录。三个淋巴瘤显示出 LOH 的证据（23%），并且在另外四个（31%）中观察到 P1DMR 的异常甲基化，尽管在正常 B 淋巴细胞中 P1 活性很低。这些数据表明，ZAC 的下调发生在 DLBCL 中，与其他癌症一样。然而，与 P1 不同，其启动子的转录抑制不是由于肿瘤中相关 CpG 岛的过度甲基化引起的。因此，ZAC 表达改变与启动子表观遗传变化之间的机制关系似乎比以前想象的更为复杂。
