This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chang, H.-C. Articles by Hung, W.-C. Search for Related Content PubMed PubMed Citation Articles by Chang, H.-C. Articles by Hung, W.-C.

Silencing of the Metastasis Suppressor RECK by RAS Oncogene Is Mediated by DNA Methyltransferase 3b–Induced Promoter Methylation

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University; ² Institute of Biomedical Sciences, National Sun Yat-Sen University; ³ National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Kaohsiung, Taiwan and ⁴ Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan

Requests for reprints: Wen-Chun Hung, Institute of Biomedical Sciences, National Sun Yat-Sen University, No. 70, Lien-Hai Road, Kaohsiung 804, Taiwan. Phone: 886-7-5252000; Fax: 886-7-5250197; E-mail: hung1228{at}ms10.hinet.net.

RECK is a membrane-anchored glycoprotein that may negatively regulate matrix metalloproteinase activity to suppress tumor invasion and metastasis. Our previous study indicated that oncogenic RAS inhibited RECK expression via a histone deacetylation mechanism. In this study, we address whether DNA methyltransferases (DNMT) participate in the inhibition of RECK by RAS. Induction of Ha-RAS^Val12 oncogene increased DNMT3b, but not DNMT1 and DNMT3a, expression in 2-12 cells. In addition, induction of DNMT3b by RAS was through the extracellular signal-regulated kinase signaling pathway. Oncogenic RAS increased the binding of DNMT3b to the promoter of RECK gene and this binding induced promoter methylation, which could be reversed by 5'-azacytidine and DNMT3b small interfering RNA (siRNA). The MEK inhibitor U0126 also reversed RAS-induced DNMT3b binding and RECK promoter methylation. Treatment of 5'-azacytidine and DNMT3b siRNA restored RECK expression in 2-12 cells and potently suppressed RAS-stimulated cell invasion. In addition, the inhibitory effect of 5'-azacytidine on RAS-induced cell invasion was attenuated after knockdown of RECK by siRNA. Interestingly, human lung cancer cells harboring constitutively activated RAS exhibited lower RECK expression and higher promoter methylation of RECK gene. 5'-Azacytidine and DNMT3b siRNA restored RECK expression in these cells and effectively suppressed invasiveness. Collectively, our results suggest that RAS oncogene induces RECK gene silencing through DNMT3b-mediated promoter methylation, and DNMT inhibitors may be useful for the treatment of RAS-induced metastasis. (Cancer Res 2006; 66(17): 8413-20)

This article has been cited by other articles:

				M.-C. Hsu, C.-C. Huang, H.-C. Chang, T.-H. Hu, and W.-C. Hung Overexpression of Jab1 in Hepatocellular Carcinoma and Its Inhibition by Peroxisome Proliferator-Activated Receptor{gamma} Ligands In vitro and In vivo Clin. Cancer Res., July 1, 2008; 14(13): 4045 - 4052. [Abstract] [Full Text] [PDF]

				M.-R. Pan, M.-F. Hou, H.-C. Chang, and W.-C. Hung Cyclooxygenase-2 Up-regulates CCR7 via EP2/EP4 Receptor Signaling Pathways to Enhance Lymphatic Invasion of Breast Cancer Cells J. Biol. Chem., April 25, 2008; 283(17): 11155 - 11163. [Abstract] [Full Text] [PDF]