Department of Gynecology, First Affiliated Hospital, China Medical University, Shenyang, PR China.
Mol Med Rep. 2011 Nov-Dec;4(6):1273-8. doi: 10.3892/mmr.2011.557. Epub 2011 Aug 16.
To investigate the contributions of histone H3 lysine 9 acetylation and DNA methylation to p16, hMLH1 and MGMT silencing in ovarian cancer cells, we treated three ovarian cancer cell lines with Trichostatin A (TSA) and 5-aza-2'-deoxycytidine and examined the status of mRNA expression, DNA methylation and histone H3 lysine 9 acetylation at the promoter of p16, hMLH1 and MGMT. The results showed that the hypermethylated silenced tumor-related genes in the ovarian cancer cells were characterized by hypoacetylated histone H3 lysine 9. Treatment with TSA resulted in the increase of histone H3 lysine 9 acetylation at the hypermethylated promoter, but with little effects on gene expression. TSA did not contribute to DNA demethylation. 5-aza-2'-deoxycytidine treatment caused DNA demethylation, increased histone H3 lysine 9 acetylation at the hypermethylated promoter and resulted in reactivation of p16, hMLH1 and MGMT. Combined treatments synergistically increased histone H3 lysine 9 acetylation accompanied by the re-expression of the hypermethylated genes. To conclude, in ovarian cancer cells, DNA methylation and histone deacetylation act synergistically for the silencing of cancer-associated genes. DNA demethylation is superior to histone acetylation for reactivating cancer-associated genes.
为了研究组蛋白 H3 赖氨酸 9 乙酰化和 DNA 甲基化对卵巢癌细胞中 p16、hMLH1 和 MGMT 沉默的贡献，我们用 Trichostatin A（TSA）和 5-氮杂-2'-脱氧胞苷处理三种卵巢癌细胞系，并检测 p16、hMLH1 和 MGMT 启动子处的 mRNA 表达、DNA 甲基化和组蛋白 H3 赖氨酸 9 乙酰化状态。结果表明，卵巢癌细胞中高度甲基化沉默的肿瘤相关基因的特征是组蛋白 H3 赖氨酸 9 低乙酰化。TSA 处理导致高度甲基化启动子处组蛋白 H3 赖氨酸 9 乙酰化增加，但对基因表达影响不大。TSA 不促进 DNA 去甲基化。5-氮杂-2'-脱氧胞苷处理导致 DNA 去甲基化，增加高度甲基化启动子处组蛋白 H3 赖氨酸 9 乙酰化，导致 p16、hMLH1 和 MGMT 重新激活。联合处理协同增加组蛋白 H3 赖氨酸 9 乙酰化，伴随着高度甲基化基因的重新表达。总之，在卵巢癌细胞中，DNA 甲基化和组蛋白去乙酰化协同作用沉默癌相关基因。DNA 去甲基化比组蛋白乙酰化更能激活癌相关基因。
