A novel mechanism in driving non-small cell lung cancer progression: The METTL3/FOXA1/PTK2 cascade

Background: Dysregulation of m6A modification has significant implications in human carcinogenesis. METTL3, a crucial m6A writer, acts as an oncogenic driver in non-small cell lung Cancer (NSCLC). Here, we explored its mechanisms in driving NSCLC development.

Methods: Cell sphere formation, invasion, Apoptosis, and proliferation were detected by sphere formation, transwell, flow cytometry, and MTT assays, respectively. Cell glycolysis was evaluated by measuring glucose consumption, lactate production, and ATP/ADP ratio. RIP, methylated RIP (MeRIP), and mRNA stability assays were used to analyze the METTL3/FOXA1 relationship. Luciferase assay and ChIP experiment were used for the evaluation of the FOXA1/PTK2 relationship. Xenograft studies were used to test the role in vivo.

Results: METTL3 was upregulated in NSCLC, and its inhibition diminished the growth, invasiveness, sphere formation ability, and glycolysis of H1299 and A549 cells. Mechanistically, METTL3 depletion caused a reduction in FOXA1 expression through the m6A modification mechanism. FOXA1 transcriptionally controlled PTK2 expression. FOXA1 upregulation reversed the effects of METTL3 inhibition on the growth, invasiveness, sphere formation ability, and glycolysis of H1299 and A549 cells. Moreover, FOXA1 increase attenuated the impact of METTL3 inhibition on the in vivo growth of A549 subcutaneous xenografts. Additionally, increased PTK2 expression counteracted the effects of FOXA1 reduction on the malignant phenotypes of H1299 and A549 cells.

Conclusion: Our finding elucidates a novel mechanism for METTL3's oncogenic activity in NSCLC, where METTL3 upregulates FOXA1 and thus activates PTK2 transcription. Blocking this cascade may be effective for combating NSCLC.

FOXA1; M6A modification; METTL3; NSCLC; Transcription factor.