M6A-dependent upregulation of ZNF460 promotes epithelial-mesenchymal transition and metastasis of gastric cancer through a histone modification-mediated positive feedback loop.

The regulatory role of TGF-β-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of N6-methyladenosine (m6A) in TGF-β signaling remains obscure. Here, we unveil, for the first time, the m6A modification profile in TGF-β-induced gastric cancer (GC) EMT and identify zinc finger protein ZNF460 as a critical mediator of the EMT process. The presence of ZNF460 greatly enhances the EMT process, as well as the invasion and spread of GC cells. Mechanistically, the activation of ZNF460 during the EMT process is mediated by METTL16-dependent m6A methylation of ZNF460 mRNA. ZNF460 interacts with histone deubiquitinase USP22 and histone demethylase PHF8 to form a stable complex, which transcriptionally activates SOX4, thereby contributing to the tumor EMT and metastasis. In addition, the ZNF460/USP22/PHF8 complex enhances the transcriptional activity of METTL16 in the nucleus, thus forming a positive feedback loop. Clinically, elevated ZNF460, alone or in combination with overexpression of METTL16 and SOX4, is predictive of poor prognosis. Collectively, our findings identify a novel oncogenic epitranscriptomic axis of METTL16/ZNF460/SOX4 which is involved in generating the EMT phenotype and regulating GC metastasis.