METTL14 Regulates PLAGL2/β-Catenin Signaling Axis to Promote the Development of Nonsmall Cell Lung Cancer

Abstract

N6-methyladenosine (m6A) is an abundant eukaryotic mRNA modification involved in regulating the formation and metastasis of nonsmall cell lung cancer (NSCLC). We collected clinical NSCLC tissue and paracarcinoma tissue. Then methyltransferase-like 14 (METTL14), pleomorphic adenoma gene like-2 (PLAGL2), and β-catenin expressions were assessed using quantitative real-time PCR and western blot. PLAGL2, and β-catenin (nuclear) expressions were increased in NSCLC tissues. Cell proliferation, migration, invasion, and death were examined. PLAGL2 could activate β-catenin signaling to affect cell proliferation and migration abilities. RNA immunoprecipitation assay was operated to identify m6A modification levels of PLAGL2 after knockdown and overexpression of METTL14. PLAGL2 was regulated by METTL14-mediated m6A modification. Knockdown of METTL14 repressed cell proliferation, migration, and invasion, and promoted cell death. Interestingly, these effects were reversed when PLAGL2 was overexpressed. Finally, tumor formation in nude mice was performed to verify the role of the METTL14/PLAGL2/β-catenin signaling axis. Tumor formation in nude mice demonstrated METTL14/PLAGL2/β-catenin axis promoted NSCLC development in vivo. In brief, METTL14 promoted NSCLC development by increasing m6A methylation of PLAGL2 to activate β-catenin signaling. Our research provided essential clues for in-depth comprehension of the mechanism of NSCLC occurrence and development and also provided the basis for NSCLC treatment.

METTL3-mediated m6A modification enhances ZDHHC16 expression in nonsmall- cell lung cancer patients, attenuating ferroptosis by suppressing CREB ubiquitination

“…The methylation process of m6A is mainly regulated by three proteins: methyltransferase (writer), demethylase (eraser), and methyl binding protein (also known as recognition protein, reader) [44]. M6Awriter is a type of enzyme that can promote the formation of m6A methylation, among which the earliest discovered m6Awriter methyltransferase 3 (METTL3) has the effect of promoting m6A formation, but cannot methylate rRNA within mRNA; Methyl transferase like 4 (METTL4) and METTL3 are homologous proteins that also promote the formation of m6A modifications [45]. In addition, as an effective component of the m6A writer complex, METTL14 can react with METTL3 to hybridize, and it is also an RNA linker protein that can enhance the activity of m6Awriter [46].…”