Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells
Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells
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DOI：
10.1074/jbc.m608525200
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发表时间：
2007-04-20
影响因子：
4.8
通讯作者：
Fang, Jing-Yuan
中科院分区：
文献类型：
--
作者：
Lu, Rong;Wang, Xia;Fang, Jing-Yuan
细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK-MAPK）通路是细胞增殖、分化和存活的关键中介。在人结肠癌细胞系SW1116中，DNA甲基转移酶1 （DNMT1）抑制剂5-aza-2′-脱氧胞苷（5-aza-dC）或ERK- mapk抑制剂PD98059或rottlerin，或瞬时转染MAP/ERK激酶（MEK）1/2小干扰RNA可下调DNMT1和增殖细胞核抗原水平。在本报告中，我们发现药物治疗或小干扰RNA转染SW1116细胞可诱导p16（INK4A）和p21（WAF1）基因启动子去甲基化，上调其mRNA和蛋白表达水平。流式细胞术显示，rotlerin诱导细胞周期阻滞于G期(1)（p < 0.05）。因此，在SW1116结肠癌细胞中，ERK-MAPK抑制剂治疗或sirna介导的ERK-MAPK敲低通过下调DNMT1表达和其他未知介质来降低DNA甲基化。
The extracellular signal-regulated kinase/mitogen-activated protein kinase ( ERK-MAPK) pathway is a critical intermediary for cell proliferation, differentiation, and survival. In the human colon cancer cell line SW1116, treatment with the DNA methyltransferase 1 ( DNMT1) inhibitor 5-aza-2'-deoxycytidine ( 5-aza-dC) or the ERK-MAPK inhibitors PD98059 or rottlerin, or transient transfection with the MAP/ERK kinase ( MEK)1/2 small interfering RNA down-regulates DNMT1 and proliferating cell nuclear antigen levels. In this report, we found that drug treatment or small interfering RNA transfection of SW1116 cells induced promoter demethylation of the p16(INK4A) and p21(WAF1) genes, which up-regulated their mRNA and protein expression levels. Flow cytometry revealed that rottlerin treatment induced cell cycle arrest at phase G(1) ( p < 0.05). Thus, the ERK-MAPK inhibitor treatment or siRNA-mediated knockdown of ERK-MAPK decreases DNA methylation via down-regulating DNMT1 expression and other unknown mediator( s) in SW1116 colon cancer cells.