METTL3-mediated m6A mRNA contributes to the resistance of carbon-ion radiotherapy in non-small-cell lung cancer.

Lung cancer is one of the leading causes of death among cancer patients worldwide. Carbon-ion radiotherapy is a radical nonsurgical treatment with high local control rates and no serious adverse events. N6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic messenger RNA (mRNA) and has important effects on the stability, splicing, and translation of mRNAs. Recently, the regulatory role of m6A in tumorigenesis has been recognized more and more. However, the dysregulation of m6A and its role in carbon-ion radiotherapy of non-small-cell lung cancer (NSCLC) remains unclear. In this study, we found that the level of methyltransferase-like 3 (METTL3) and its mediated m6A modification were elevated in NSCLC cells with carbon-ion radiotherapy. Knockdown of METTL3 in NSCLC cells impaired proliferation, migration, and invasion in vitro and in vivo. Moreover, we found that METTL3-mediated m6A modification of mRNA inhibited the decay of H2A histone family member X (H2AX) mRNA and enhanced its expression, which led to enhanced DNA damage repair and cell survival.