METTL3-induced DLGAP1-AS2 promotes non-small cell lung cancer tumorigenesis through m ⁶ A/c-Myc-dependent aerobic glycolysis

Abstract

The critical roles of N⁶-methyladenosine (m⁶A) modification have been demonstrated by more and more evidence. However, the cross talk of m⁶A and long noncoding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) tumorigenesis is still unclear. Here, this work focused on the functions and molecular mechanism of m⁶A-modified lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) in NSCLC. Microarray analysis found that lncRNA DLGAP1-AS2 is upregulated in NSCLC cells. Clinical data showed that DLGAP1-AS2 high-expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 overexpression promoted the aerobic glycolysis and DLGAP1-AS2 knockdown suppressed the tumor growth of NSCLC cells. Mechanistically, m⁶A methyltransferase METTL3 enhanced the stability of DLGAP1-AS2 via m⁶A site binding. Moreover, DLGAP1-AS2 interacted with YTHDF1 to enhance the stability of c-Myc mRNA through DLGAP1-AS2/YTHDF1/m⁶A/c-Myc mRNA. In conclusion, our work indicates the functions of m⁶A-modified DLGAP1-AS2 in the NSCLC aerobic glycolysis, disclosing a potential m⁶A-dependent manner for NSCLC treatment.