A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer
A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer
复制标题
DOI：
10.1038/ng892
复制
发表时间：
2002-06-01
期刊：
影响因子：
30.8
通讯作者：
Baylin, SB
中科院分区：
文献类型：
--
作者：
Suzuki, H;Gabrielson, E;Baylin, SB
基因启动子异常甲基化是肿瘤抑制基因失活的主要机制。我们以前表明，这种转录沉默介导的甲基化和组蛋白脱乙酰酶活性，甲基化是占主导地位的。在这里，我们使用cDNA微阵列分析来筛选在人类结直肠癌中表观遗传学沉默的基因。通过筛选超过10，000个基因，我们表明我们的方法可以在给定的癌症中识别出大量具有启动子高甲基化的基因;这些基因与具有非甲基化启动子的基因不同，对于非甲基化启动子，单独通过组蛋白去乙酰化酶抑制产生表达增加。我们发现的许多高甲基化基因由于其预测的功能和染色体位置而在肿瘤发生中具有很高的作用潜力。我们还鉴定了一组在结直肠癌和胃癌中优先高甲基化的基因。这些基因之一，SFRP 1，属于一个基因家族，我们表明，在这个家庭中的四个基因的超甲基化发生在结直肠癌中非常频繁，提供（i）一个独特的潜在机制的肿瘤抑制基因功能的损失和（ii）构建一个分子标记面板，可以检测几乎所有的结直肠癌。
Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.