Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation
Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation
复制标题
DOI：
10.1038/sj.onc.1207050
复制
发表时间：
2003-12-04
期刊：
影响因子：
8
通讯作者：
Dent, SYR
中科院分区：
文献类型：
--
作者：
Coombes, MM;Briggs, KL;Dent, SYR
头颈部鳞状细胞癌（HNSCC）是美国第五常见的癌症。几种遗传和表观遗传改变与HNSCC肿瘤发生相关，包括通过DNA甲基化在细胞系和原发性肿瘤中编码p16肿瘤抑制因子的CDKN 2A失活。通过DNA去甲基化剂和组蛋白去乙酰化酶（HDAC）抑制剂重新激活肿瘤抑制基因显示了对其他癌症的治疗前景。因此，我们研究了这些药物在Tu 159 HNSCC细胞中重新激活p16的能力。用5-氮杂-2 '脱氧胞苷（5-aza-dC）处理细胞增加CDKN 2A表达，并略微增加该基因处的组蛋白H3乙酰化。在用HDAC抑制剂曲马斯他汀A（TSA）处理后未观察到CDKN 2A的再活化，但在用5-aza-dC和TSA相继处理Tu 159细胞后观察到CDKN 2A的协同再活化。Tu 159细胞中CDKN 2A的沉默与组蛋白H3在赖氨酸9的甲基化增加和相对于上游p15基因启动子的赖氨酸4的甲基化减少相关。有趣的是，H3-K9甲基化的总体水平在用5-aza-dC处理后降低。总之，这些数据表明，DNA甲基化是Tu 159肿瘤细胞中CDKN 2A沉默的显性表观遗传标记。此外，DNA甲基化的变化可以通过影响多个H3修饰来重置组蛋白密码。
Head and neck squamous cell carcinoma (HNSCC) is the fifth most frequent cancer in the US. Several genetic and epigenetic alterations are associated with HNSCC tumorigenesis, including inactivation of CDKN2A, which encodes the p16 tumor suppressor, in cell lines and primary tumors by DNA methylation. Reactivation of tumor suppressor genes by DNA-demethylating agents and histone deacetylase (HDAC) inhibitors shows therapeutic promise for other cancers. Therefore, we investigated the ability of these agents to reactivate p16 in Tu159 HNSCC cells. Treatment of cells with 5-aza-2' deoxycytidine (5-aza-dC) increases CDKN2A expression and slightly increases histone H3 acetylation at this gene. No reactivation of CDKN2A is observed upon treatment with the HDAC inhibitor trichostatin A (TSA), but synergistic reactivation of CDKN2A is observed upon sequential treatment of Tu159 cells with both 5-aza-dC and TSA. Silencing of CDKN2A in Tu159 cells is correlated with increased methylation of histone H3 at lysine 9 and decreased methylation at lysine 4 relative to the upstream p15 gene promoter. Interestingly, global levels of H3-K9 methylation are decreased upon treatment with 5-aza-dC. Together these data indicate that DNA methylation is a dominant epigenetic mark for silencing of CDKN2A in Tu159 tumor cells. Moreover, changes in DNA methylation can reset the histone code by impacting multiple H3 modifications.