METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma

Abstract

Understanding the role of N6-methyladenosine (m⁶A) in tumorigenesis and stem cell maintenance is an emerging field in glioma research. However, it is necessary to study the function of m⁶A in IDH-mutation and IDH-wildtype gliomas separately. Here, we aimed to elucidate the role and mechanism of the m⁶A writer METTL3 in regulating the malignant progression of IDH-wildtype gliomas. We demonstrated that METTL3 expression is positively associated with a higher malignant grade and poorer prognosis of IDH-wildtype gliomas but not IDH-mutant gliomas. METTL3 could also promote the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, METTL3 upregulated MALAT1 expression by enhancing its stability via m⁶A modification. We further revealed that HuR was essential for METTL3-mediated MALAT1 stabilization, and upregulated MALAT1 subsequently activated NF-κB. Taken together, our findings confirmed that METTL3 promoted the malignant progression of IDH-wildtype gliomas and revealed important insight into the upstream regulatory mechanism of MALAT1 and NF-κB with a primary focus on m6A modification.

Keywords: Glioma; LncRNA; METTL3; NF-κB; RNA modification.