Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma.

Abstract

Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evidence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the development of NPC. In particular, the EBV principal oncogene, latent membrane protein 1 (LMP1), is considered a key factor in inducing aberrant DNA methylation of several tumour suppressor genes in NPC, although the mechanism remains unclear. Herein, we comprehensively analysed the methylome data of Infinium BeadArray from 51 NPC and 52 normal nasopharyngeal tissues to identify LMP1-inducible methylation genes. Using hierarchical clustering analysis, we classified NPC into the high-methylation, low-methylation, and normal-like subgroups. We defined high-methylation genes as those that were methylated in the high-methylation subgroup only and common methylation genes as those that were methylated in both high- and low-methylation subgroups. Subsequently, we identified 715 LMP1-inducible methylation genes by observing the methylome data of the nasopharyngeal epithelial cell line with or without LMP1 expression. Because high-methylation genes were enriched with LMP1-inducible methylation genes, we extracted 95 high-methylation genes that overlapped with the LMP1-inducible methylation genes. Among them, we identified DERL3 as the most significantly methylated gene affected by LMP1 expression. DERL3 knockdown in cell lines resulted in significantly increased cell proliferation, migration, and invasion. Lower DERL3 expression was more frequently detected in the advanced T-stage NPC than in early T-stage NPC. These results indicate that DERL3 repression by DNA methylation contributes to NPC tumour progression.

• Authors: Satoru Kondo, Atsushi Okabe, Takuya Nakagawa, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Hirotomo Dochi, Harue Mizokami, Yuki Kitagawa, Tomoya Kurokawa, Masato Mima, Kazuhira Endo, Hisashi Sugimoto, Naohiro Wakisaka, Kiyoshi Misawa, Tomokazu Yoshizaki, Atsushi Kaneda
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1869 Issue 2 Pg. 166598 (02 2023) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 36372158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• DERL3 protein, human
• EBV-associated membrane antigen, Epstein-Barr virus
• Membrane Proteins

Topics

• Humans
• DNA Methylation
• Epstein-Barr Virus Infections (metabolism)
• Herpesvirus 4, Human (genetics)
• Membrane Proteins (genetics)
• Nasopharyngeal Carcinoma (genetics, virology)
• Nasopharyngeal Neoplasms (genetics, virology)
• Gene Expression Regulation, Neoplastic