Abstract
BackgroundN6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.MethodsThe expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.ResultsThe results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc−, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.ConclusionsThese findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.
Highlights
N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers
The methyltransferase-like 3 (METTL3)-mediated methylation of solute carrier 7A11 (SLC7A11) could regulate the stability and translation of SLC7A11 mRNA through YTHDF1 recruitment in lung adenocarcinoma (LUAD) cells. We found that both the expression of YTHDF1 and SLC7A11 were elevated and positively related to METTL3 and m 6A levels in LUAD samples, which indicated that METTL3mediated m6A modification of SLC7A11 illustrated a significant role in human LUAD progression and ferroptosis pathways
METTL3‐mediated m6A modification is elevated in LUAD patients and nonsmall-cell lung cancer (NSCLC) cells To investigate the role of m 6A modification in LUAD, we first evaluated the m 6A level in LUAD tissues by immunohistochemistry (IHC)
Summary
N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. We explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m 6A, in LUAD progression. Despite advances in cancer progression and treatment, lung cancer remains occupying the leading cause of cancer-related mortalities worldwide, with an estimated 2.2 million new cases and 1.8 million deaths per year [1, 2]. Alteration of m 6A participates in regulating mRNA splicing, export, translation, and stability, which involves three components, including methyltransferases (writers), demethylases (erasers) and RNA-binding proteins (readers) [8]. The biological significance and underlying mechanism of m6A in LUAD remain elusive
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