Abstract
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.
Highlights
ERK2 (ERK1/2) in this pathway modulate a wide variety of cellular activities via the regulation of several transcription factors
MTT assays showed that treatment of SW1116 cells with the protein kinase C (PKC)-␦ inhibitor rottlerin resulted in a significant inhibition of growth starting from 24 h at 20 mol/liter
Our results indicated that RNAi-induced MEK1 or MEK2 deficiencies inhibited SW1116 cell growth, which declined maximally 24 h after transfection
Summary
ERK2 (ERK1/2) in this pathway modulate a wide variety of cellular activities via the regulation of several transcription factors. Several reports have shown that two ERK-MAPK inhibitors, procainamide and hydralazine, produce hypomethylation in T cell lines (4, 15–17) These observations have led to efforts to use these drugs to demethylate tumor suppressor genes in cancer cells. The mechanism whereby these ERK-MAPK pathway inhibitors affect DNA methylation that silences gene transcription in cancer, in human colon cancer, is poorly understood. The effect of the PKC-␦ inhibitor rottlerin (18) on tumor-related gene regulation and the cell cycle in human colon cancer cell lines is unknown. The aim of this study was to further elucidate the etiological association of the ERK-MAPK pathway and methylation in human colon cancer, and to investigate the extent of the loss of MAP/ERK kinases (MEK) 1 and 2 and the effects of ERK signaling on cell proliferation and cycling. We investigated the mediating mechanisms of ERK-MAPK on DNA methylation
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