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J. Biol. Chem., Vol. 282, Issue 16, 12249-12259, April 20, 2007

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Inhibition of the Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway Decreases DNA Methylation in Colon Cancer Cells^*

From the Shanghai Jiaotong University School of Medicine, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai 200001, China

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 G₁ (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.

Received for publication, September 5, 2006 , and in revised form, February 16, 2007.

^* This work was supported by National Basic Research Program of China 973 program Grant 2005CB522400, Shanghai Leading Academic Discipline Project Grant Y0205, and Shanghai Municipal Commission for Science and Technology Grant 04DZ14006 (to J.-Y. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: 145 Shandong Road Middle, Shanghai 200001, China. Tel.: 86-21-63200874; Fax: 86-21-63266027; E-mail: jingyuanfang{at}yahoo.com.

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