DDX3X forms a complex with METTL3 to promote glioma progression via tumor immune microenvironment remodeling

Abstract

Methyltransferase-like 3 (METTL3) is the key catalytic subunit of the N6-adenosine methyltransferase complex regulating N6-methyladenosine (m6A) modification of mRNA in mammalian cells. Although METTL3 expression is elevated in multiple cancers, the regulatory mechanisms are still poorly understood. Here, we found that DDX3X interacts with METTL3 and regulates its enzyme activity, which increases the m6A modification of CCL2. DDX3X knockdown attenuates CCL2 expression and the infiltration of tumor-associated macrophages and inhibits glioma progression depending on tumor immune microenvironment remodeling. Moreover, METTL3 inhibition abolishes the DDX3X-driven acceleration of tumor growth. Further analysis showed that DDX3X enhances CCL2 expression in a manner of m6A-IGF2BP2. DDX3X inhibition combines with METTL3 blockage obviously impedes glioma progression. Clinically, increased DDX3X expression is closely associated with glioma progression and is positively correlated with METTL3, CCL2 and CD68 expression in glioma patient tissues. In summary, our research demonstrates the potential role of DDX3X-METTL3-CCL2 axis in glioma progression, providing the possible new target for the treatment of glioma.