A genome-wide screen for differentially methylated long noncoding RNAs identified that lncAC007255.8 is regulated by promoter DNA methylation in Beas-2B cells malignantly transformed by NNK
A genome-wide screen for differentially methylated long noncoding RNAs identified that lncAC007255.8 is regulated by promoter DNA methylation in Beas-2B cells malignantly transformed by NNK
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对差异甲基化长非编码 RNA 的全基因组筛选发现，在 NNK 恶性转化的 Beas-2B 细胞中，lncAC007255.8 受到启动子 DNA 甲基化的调节
DOI：
10.1016/j.toxlet.2021.04.013
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发表时间：
2021-04-28
影响因子：
3.5
通讯作者：
Yang, Qiaoyuan
中科院分区：
文献类型：
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作者：
Chen, Enzhao;Zhou, Jiaxin;Yang, Qiaoyuan
众所周知，烟草暴露会诱发导致肺癌发病机制的遗传和表观遗传变化。4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）是一种重要的烟草特异性致癌物，但其致癌机制尚未完全阐明。在这项研究中，我们发现DNA甲基转移酶1 （DNMT1）在NNK诱导的恶性转化的人支气管上皮Beas-2B细胞（2B-NNK细胞）中，通过NNK （400 mg/mL）处理7天，DNA甲基转移酶1 （DNMT1）过表达。使用Arraystar人类非编码RNA启动子芯片检测长链非编码RNA （lncRNAs）启动子区域的DNA甲基化状态。结果表明，在lncRNA启动子区域存在1010个差异甲基化片段。QRT-PCR结果显示，lncRNA AC007255.8在2B-NNK细胞和肺癌组织中表达显著下调。此外，甲基化特异性PCR显示，在2B-NNK细胞和肺癌组织中，lncRNA AC007255.8启动子的甲基化增加。lncRNA AC007255.8的表达降低与lncRNA AC007255.8启动子区域的高甲基化显著相关。LncRNA AC007255.8过表达可导致2B-NNK细胞增殖能力下降，细胞凋亡增加。综上所述，在Beas-2B细胞中，NNK通过上调DNMT1诱导lncRNA AC007255.8启动子超甲基化，导致lncRNA AC007255.8下调，最终促进细胞增殖，抑制细胞凋亡。这项研究为肺癌的表观遗传机制提供了新的见解，并将刺激进一步研究基因组非编码区异常DNA甲基化在肺癌发病机制中的作用。(C) 2021 Elsevier B.V.版权所有
Tobacco exposure is well known to induce genetic and epigenetic changes that contribute to the pathogenesis of lung cancer. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a significant tobacco-specific carcinogen, but the oncogenic mechanisms of NNK have not been thoroughly elucidated. In this study we found that DNA methyltransferase 1 (DNMT1) was overexpressed in malignantly transformed human bronchial epithelial Beas-2B cells induced by NNK (2B-NNK cells), by treatment with NNK (400 mg/mL) for 7 days. An Arraystar Human noncoding RNA Promoter Microarray was used to detect the DNA methylation status of the promoter region of long noncoding RNAs (lncRNAs). The result showed that 1010 differentially methylated fragments were present in the lncRNA promoter region. QRT-PCR revealed that the expression of lncRNA AC007255.8 was remarkably downregulated in 2B-NNK cells and lung cancer tissues. Furthermore, Methylation-specific PCR showed that the methylation of the lncRNA AC007255.8 promoter was increased in 2B-NNK cells and lung cancer tissues. The reduced expression of lncRNA AC007255.8 was significantly associated with hypermethylation of lncRNA AC007255.8 promoter region. LncRNA AC007255.8 overexpression could result in decreased cell proliferation and increased cell apoptosis in 2B-NNK cells. In conclusion, NNK induced lncRNA AC007255.8 promoter hypermethylation via upregulation of DNMT1 in Beas-2B cells, leading to downregulation of lncRNA AC007255.8, and ultimately the enhancement of cell proliferation and the inhibition of apoptosis. This research affords novel insights into the epigenetic mechanisms of lung cancer, and will stimulate further research into the involvement of aberrant DNA methylation of noncoding regions of the genome in the pathogenesis of lung cancer. (C) 2021 Elsevier B.V. All rights reserved.