METTL14通过调节铁死亡和GPX4的m6A修饰在非小细胞肺癌中发挥致癌作用。

METTL14 plays an oncogenic role in NSCLC by modulating ferroptosis and the m6A modification of GPX4.

作者信息

Lou Yang, Huang Kan, Xu Bo, Chen Xianguo

机构信息

Department of Cardiothoracic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China.

出版信息

Arch Physiol Biochem. 2024 Dec;130(6):962-973. doi: 10.1080/13813455.2024.2376813. Epub 2024 Jul 11.

DOI:10.1080/13813455.2024.2376813

PMID:38993012

Abstract

CONTEXT

N6-methyladenosine (m6A) of RNA is involved in the progression of non-small cell lung cancer (NSCLC).

OBJECTIVE

This study investigated the role of METTL14 in NSCLC and the mechanism.

MATERIALS AND METHODS

Expression levels were assessed by quantitative real-time PCR and ELISA assays. Cells viability was assessed by cell counting kit-8. M6A methylation was analysed by methylated RNA immunoprecipitation (MeRIP), RIP, luciferase assay, and mRNA stability assay.

RESULTS

The results showed that METTL14 was highly expressed in NSCLC tissues and cell lines. Knockdown of METTL14 inhibited the cell viability while induced ferroptosis of NSCLC cells. Mechanistically, METTL14 interacts with GPX4, mediates m6A modification of GPX4, enhances its mRNA stability, and upregulates its expression. In addition, IGF2BP1 recognises the m6A-methylated GPX4 and mediates the elevated mRNA stability. Moreover, GPX4 reversed the effects of METTL14 depletion.

DISCUSSION AND CONCLUSION

The METTL14/GPX4 axis promotes NSCLC progression by inhibiting cell ferroptosis through the recognition of m6A modification mediated by IGF2BP1.

摘要

背景

RNA的N6-甲基腺苷（m6A）参与非小细胞肺癌（NSCLC）的进展。

目的

本研究探讨METTL14在NSCLC中的作用及其机制。

材料与方法

通过定量实时PCR和ELISA检测评估表达水平。使用细胞计数试剂盒-8评估细胞活力。通过甲基化RNA免疫沉淀（MeRIP）、RIP、荧光素酶测定和mRNA稳定性测定分析m6A甲基化。

结果

结果显示METTL14在NSCLC组织和细胞系中高表达。敲低METTL14可抑制细胞活力，同时诱导NSCLC细胞发生铁死亡。机制上，METTL14与GPX4相互作用，介导GPX4的m6A修饰，增强其mRNA稳定性，并上调其表达。此外，IGF2BP1识别m6A甲基化的GPX4并介导mRNA稳定性升高。而且，GPX4可逆转METTL14缺失的影响。