Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma
Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma
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DOI：
10.1016/j.bbadis.2022.166598
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发表时间：
2022-11-18
影响因子：
6.2
通讯作者：
Kaneda, Atsushi
中科院分区：
文献类型：
--
作者：
Kondo, Satoru;Okabe, Atsushi;Kaneda, Atsushi
鼻咽癌（NPC）是与EB病毒（EB病毒）相关的侵袭性恶性肿瘤。越来越多的证据表明，包括DNA甲基化在内的表观遗传异常在鼻咽癌的发生发展中起着重要作用。特别是，EB病毒的主要致癌基因，潜伏膜蛋白1（LMP1），被认为是一个关键因素，在诱导异常的DNA甲基化的几个肿瘤抑制基因在NPC，虽然机制尚不清楚。在此，我们全面分析了来自51例NPC和52例正常鼻咽组织的Infinium BeadArray的甲基化组数据，以确定LMP1诱导的甲基化基因。运用聚类分析将鼻咽癌分为高甲基化、低甲基化和正常样亚组。我们将仅在高甲基化亚组中甲基化的基因定义为高甲基化基因，将在高甲基化亚组和低甲基化亚组中均甲基化的基因定义为常见甲基化基因。随后，我们通过观察有或没有LMP1表达的鼻咽上皮细胞系的甲基化组数据，鉴定了715个LMP1诱导的甲基化基因。由于高甲基化基因富含LMP1诱导的甲基化基因，我们提取了95个与LMP1诱导的甲基化基因重叠的高甲基化基因。其中，我们确定DERL 3是受LMP 1表达影响最显著的甲基化基因。细胞系中的DERL 3敲低导致细胞增殖、迁移和侵袭显著增加。DERL 3的低表达在晚期T期NPC中比在早期T期NPC中更常见。这些结果表明，DNA甲基化对DERL 3的抑制有助于NPC肿瘤的进展。
Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evi-dence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the devel-opment 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 hi-erarchical 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 sub -group 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.