Activation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH 2-terminal kinase signaling

Chia Lung Tsai, Hsin Pai Li, Yen Jung Lu, Chuen Hsueh, Ying Liang, Chi Long Chen, Sai Wah Tsao, Ka Po Tse, Jau Song Yu, Yu Sun Chang

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

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 IκB, 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 κB 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.

Original languageEnglish
Pages (from-to)11668-11676
Number of pages9
JournalCancer Research
Volume66
Issue number24
DOIs
Publication statusPublished - Dec 15 2006

    Fingerprint

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tsai, C. L., Li, H. P., Lu, Y. J., Hsueh, C., Liang, Y., Chen, C. L., Tsao, S. W., Tse, K. P., Yu, J. S., & Chang, Y. S. (2006). Activation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH 2-terminal kinase signaling. Cancer Research, 66(24), 11668-11676. https://doi.org/10.1158/0008-5472.CAN-06-2194