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Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH₂-Terminal Kinase Signaling

¹ Graduate Institute of Basic Medical Sciences and ² Pathology Core, Chang-Gung Molecular Medicine Research Center, Chang-Gung University; Departments of ³ Medical Research and ⁴ Pathology, Chang-Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan, Republic of China; ⁵ Institute of Microbiology and Immunology, National Yang-Ming University; ⁶ Department of Pathology, Taipei Medial University, Taipei, Taiwan, Republic of China; and ⁷ Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong

Requests for reprints: Yu-Sun Chang, Graduate Institute of Basic Medical Sciences, Chang-Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Taoyuan 333, Taiwan, Republic of China. Phone: 886-3-211-8683; Fax: 886-3-211-8683; E-mail: ysc{at}mail.cgu.edu.tw.

EBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH₂-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor–associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor B and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1. (Cancer Res 2006; 66(24): 11668-76)

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