METTL1 Mediated m7G Modification Regulates Ferroptosis and Chemotherapy Resistance via Involvement of pri-miR-26a/FTH1 Axis in Osteosarcoma

Abstract Background N7-Methyladenosine (m7G), one of the most prevalent internal modifications in mammalian RNAs, makes a great contribution to many bioprocesses. However, its functions and underlying mechanisms in the occurrence and development of osteosarcoma remain elusive. Methods The expression of METTL1 and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset.Targets of METTL1 on osteosarcoma were identified by AlkAniline-seq, RNA immunoprecipitation (RIP), quantitative real-time PCR, western blot and luciferase assays. The effects of METTL1 on the biological characteristics of osteosarcoma cells were investigated on the basis of gain- and loss-of-function analyses. Ferroptosis were analyzed by lipid peroxidation assay, iron assay and ransmission electron microscopy (TEM). Subcutaneous models further uncovered the role of METTL1 in tumour growth. Results Here, we have identified that METTL1, an m7G methyltransferase, is low expressed in osteosarcoma tissues and plays an antitumor role in osteosarcoma. Mechanistically, METTL1 enhances cell ferroptosis by targeting pri-miR-26a and promoting its mature through m7G methylation, which could target FTH1 mRNA and eliminate FTH1 translation efficiency mediated by METTL1. FTH1 is the main component of ferritin which is crucial for iron homeostasis and the inhibition of lipid peroxidation. Reduction of FTH1 translation dramatically increases ferroptosis and enhances osteosarcoma chemosensitivity. Conclusions Collectively, our study demonstrates the METTL1/pri-miR-26a/FTH1 axis signaling in osteosarcoma and highlights the functional importance of METTL1 and m7G methylation in the progression and chemotherapy resistance of osteosarcoma, suggesting that reprogramming RNA m7G methylation as a potential and promising strategy for osteosarcoma treatment.