Wu Weidong, Li Mengling, Wu Yingxiao, Wei Qiongying, Yu Nanding
Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical University, Fuzhou, 350122, Fujian, China.
Cell Death Discov. 2024 Aug 13;10(1):361. doi: 10.1038/s41420-024-02133-w.
METTL14 functions as an RNA methyltransferase involved in m6A modification, influencing mRNA biogenesis, decay, and translation processes. However, the specific mechanism by which METTL14 regulates glucose-6-phosphate dehydrogenase (G6PD) to promote the progression of lung adenocarcinoma (LUAD) is not well understood. Quantitative measurement and immunohistochemistry (IHC) analysis have demonstrated higher levels of m6A in LUAD tissues compared to adjacent normal tissues. Additionally, the expression of METTL14 was significantly increased in LUAD tissues. In LUAD cell lines, both METTL14 and m6A levels were elevated compared to normal human lung epithelial cells. Knockdown of METTL14 markedly reduced LUAD cell proliferation, migration, and invasion. Conversely, overexpression of METTL14, but not the mutant form, significantly enhanced these cellular processes in LUAD. In vivo studies using nude mice with subcutaneously transplanted LUAD cells demonstrated that stable METTL14 knockdown led to notably reduced tumor volume and weight, along with fewer Ki67-positive cells and lung metastatic sites. Importantly, METTL14 knockdown reduced glycolytic activity in LUAD cells. Through a combination of RNA sequencing and MeRIP-sequencing, we identified numerous altered genes and confirmed that IGF2BP2 enhances G6PD mRNA stability after METTL14-mediated m6A modification, thereby promoting tumor growth and metastasis. Moreover, LUAD patients with higher levels of G6PD had poorer overall survival (OS). In conclusion, our study indicates that METTL14 upregulates G6PD expression post-transcriptionally through an m6A-IGF2BP2-dependent mechanism, thereby stabilizing G6PD mRNA. These findings propose potential diagnostic biomarkers and effective targets for anti-metabolism therapy in LUAD.
METTL14作为一种参与m6A修饰的RNA甲基转移酶发挥作用，影响mRNA的生物合成、降解和翻译过程。然而，METTL14调节葡萄糖-6-磷酸脱氢酶（G6PD）以促进肺腺癌（LUAD）进展的具体机制尚不清楚。定量测量和免疫组织化学（IHC）分析表明，与相邻正常组织相比，LUAD组织中m6A水平更高。此外，METTL14在LUAD组织中的表达显著增加。在LUAD细胞系中，与正常人肺上皮细胞相比，METTL14和m6A水平均升高。敲低METTL14显著降低了LUAD细胞的增殖、迁移和侵袭。相反，METTL14的过表达（而非突变形式）显著增强了LUAD中的这些细胞过程。使用皮下移植LUAD细胞的裸鼠进行的体内研究表明，稳定敲低METTL14导致肿瘤体积和重量显著减小，Ki67阳性细胞和肺转移位点减少。重要的是，敲低METTL14降低了LUAD细胞中的糖酵解活性。通过RNA测序和MeRIP测序相结合，我们鉴定了许多改变的基因，并证实IGF2BP2在METTL14介导的m6A修饰后增强了G6PD mRNA的稳定性，从而促进肿瘤生长和转移。此外，G6PD水平较高的LUAD患者总生存期（OS）较差。总之，我们的研究表明，METTL14通过m6A-IGF2BP2依赖性机制在转录后上调G6PD表达，从而稳定G6PD mRNA。这些发现为LUAD提出了潜在的诊断生物标志物和抗代谢治疗的有效靶点。
