Yang Qin, Zhu Lin, Ye Mao, Zhang Bin, Zhan Peihe, Li Hui, Zou Wen, Liu Jing
Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
School of Medical Laboratory, Shao Yang University, Shaoyang, China.
Front Genet. 2022 Jun 20;13:805960. doi: 10.3389/fgene.2022.805960. eCollection 2022.
Non-small-cell lung cancer (NSCLC) is divided into three major histological types, namely, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large-cell lung carcinoma (LCLC). We previously identified that 4.1N/ acts as a tumor suppressor and is reduced in NSCLC patients. In the current study, we explored the underlying epigenetic mechanisms of 4.1N/ reduction in NSCLC. The 4.1N/ gene promoter region was highly methylated in LUAD and LUSC patients. LUAD patients with higher methylation level in the 4.1N/ gene promoter (TSS1500, cg13399773 or TSS200, cg20993403) had a shorter overall survival time (Log-rank = 0.02 HR = 1.509 or Log-rank = 0.016 HR = 1.509), whereas LUSC patients with higher methylation level in the 4.1N/ gene promoter (TSS1500 cg13399773, TSS1500 cg07030373 or TSS200 cg20993403) had a longer overall survival time (Log-rank = 0.045 HR = 0.5709, Log-rank = 0.018 HR = 0.68 or Log-rank = 0.014 HR = 0.639, respectively). High methylation of the 4.1N/ gene promoter appeared to be a relatively early event in LUAD and LUSC. DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine restored the 4.1N/ expression at both the mRNA and protein levels. MiR-454-3p was abnormally highly expressed in NSCLC and directly targeted 4.1N/ mRNA. MiR-454-3p expression was significantly correlated with 4.1N/ expression in NSCLC patients (r = -0.63, < 0.0001). Therefore, we concluded that promoter hypermethylation of the 4.1N/ gene and abnormally high expressed miR-454-3p work at different regulation levels but in concert to restrict 4.1N/ expression in NSCLC. Taken together, this work contributes to elucidate the underlying epigenetic disruptions of 4.1N/ deficiency in NSCLC.
非小细胞肺癌（NSCLC）分为三种主要组织学类型，即肺腺癌（LUAD）、肺鳞状细胞癌（LUSC）和大细胞肺癌（LCLC）。我们之前发现4.1N/起肿瘤抑制作用，且在NSCLC患者中表达降低。在本研究中，我们探究了NSCLC中4.1N/表达降低的潜在表观遗传机制。4.1N/基因启动子区域在LUAD和LUSC患者中高度甲基化。4.1N/基因启动子（TSS1500，cg13399773或TSS200，cg20993403）甲基化水平较高的LUAD患者总生存时间较短（对数秩检验 = 0.02，风险比 = 1.509或对数秩检验 = 0.016，风险比 = 1.509），而4.1N/基因启动子（TSS1500 cg13399773、TSS1500 cg07030373或TSS200 cg20993403）甲基化水平较高的LUSC患者总生存时间较长（对数秩检验 = 0.045，风险比 = 0.5709；对数秩检验 = 0.018，风险比 = 0.68；或对数秩检验 = 0.014，风险比 = 0.639）。4.1N/基因启动子的高甲基化似乎是LUAD和LUSC中相对早期的事件。DNA甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷在mRNA和蛋白质水平均恢复了4.1N/的表达。MiR-454-3p在NSCLC中异常高表达，并直接靶向4.1N/ mRNA。NSCLC患者中MiR-454-3p表达与4.1N/表达显著相关（r = -0.63，P < 0.0001）。因此，我们得出结论，4.1N/基因启动子高甲基化和异常高表达的MiR-454-3p在不同调控水平协同作用，限制NSCLC中4.1N/的表达。综上所述，这项工作有助于阐明NSCLC中4.1N/缺乏的潜在表观遗传破坏机制。
