Department of Respiratory Diseases, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, People's Republic of China.
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Chang-Le Xi Street #169, Xi'an, 710032, People's Republic of China.
J Exp Clin Cancer Res. 2021 Mar 6;40(1):90. doi: 10.1186/s13046-021-01880-3.
FBXW7 mA modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.
The correlation between FBXW7 and various genes related to mA modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA mA modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 mA modification on LUAD development.
Decreased FBXW7 expression was accompanied by downregulated METTL3 expression in human LUAD tissues and was associated with a worse prognosis for LUAD in The Cancer Genome Atlas database. mA was highly enriched in METTL3-mediated FBXW7 transcripts, and increased mA modification in the coding sequence region increased its translation. Functionally, METTL3 overexpression or knockdown affected the apoptosis and proliferation phenotype of LUAD cells by regulating FBXW7 mA modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored LUAD cell suppression in vitro and in vivo.
Our findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of mA-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.
FBXW7 mA 修饰在肺腺癌（LUAD）进展中起着重要作用；然而，其潜在机制尚不清楚。
使用癌症基因组图谱数据库分析 FBXW7 与各种与 mA 修饰相关的基因之间的相关性。在细胞模型中检测 METTL3 对 FBXW7 mRNA mA 修饰的调节作用，并通过甲基化 RNA 免疫沉淀、RNA 免疫沉淀、荧光素酶报告和突变分析确定其潜在机制。进行体外实验以进一步探讨 METTL3 介导的 FBXW7 mA 修饰对 LUAD 发展的生物学影响。
在人类 LUAD 组织中，FBXW7 表达降低伴随着 METTL3 表达降低，并且在癌症基因组图谱数据库中与 LUAD 的预后不良相关。mA 在 METTL3 介导的 FBXW7 转录本中高度富集，并且编码序列区域中 mA 修饰的增加增加了其翻译。功能上，METTL3 的过表达或敲低通过调节 FBXW7 mA 修饰和表达影响 LUAD 细胞的凋亡和增殖表型。此外，在 METTL3 耗尽的细胞中过表达 FBXW7 部分恢复了 LUAD 细胞在体外和体内的抑制作用。
我们的研究结果表明，METTL3 正向调节 FBXW7 的表达，并证实了 mA 修饰的 FBXW7 的肿瘤抑制作用，从而深入了解其在 LUAD 起始和发展中的表观遗传调控机制。
