METTL14 attenuates cancer stemness by suppressing ATF5/WDR74/β-catenin axis in gastric cancer

Abstract Purpose Stemness is one of the leading causes of treatment failure in gastric cancer (GC). Methyltransferase-like 14 (METTL14) participates in several malignancies. But the precise mechanisms of METTL14 in regulating GC stemness are still unclear. Methods Expression of METTL14 in GC was assessed by public datasets and clinical specimens. The roles of METTL14 in proliferation, metastasis and stemness were examined by using both in vitro and in vivo experiments. The m6A RNA immunoprecipitation (MeRIP) and luciferase reporter assays were performed to verify the target of METTL14. Rescue assays were used to explore the impaired stemness by METTL14 overexpression. The downstream mechanisms of ATF5 and upstream modification of METTL14 were studied by Chromatin immunoprecipitation (ChIP) and westernblot. Results Decreased expression of METTL14 was correlated with poor survival in GC. Functionally, METTL14 knockdown promoted GC cell stemness. Mechanically, METTL14 mediated m6A modification and facilitated ATF5 mRNA degradation. Furthermore, the deleterious effects subdued by the overexpression of METTL14 were restored following ATF5 overexpression, which facilitated the transcription of WDR74, thereby enhancing β-catenin translocation from the cytoplasm to the nucleus. Moreover, lactylation modification that occurred on the histone H3 (Lys18) of METTL14 could promote the expression of METTL14. Conclusions Our results demonstrate that METTL14 knockdown-mediated m6A modification of ATF5 mRNA promotes GC stemness by activating the WDR74/β-catenin axis.