WTAP mediates FOXP3 mRNA stability to promote SMARCE1 expression and augment glycolysis in colon adenocarcinoma

N6-methyladenosine (m6A) is the most abundant mRNA internal modification and has reportedly been linked to aerobic glycolysis, a hallmark event in tumor development. This work focuses on the role of the m6A methyltransferase WT1-associated protein (WTAP) in metabolic reprogramming and development of colon adenocarcinoma (COAD) and the molecules involved. The WTAP expression in COAD tissues and cells was detected. WTAP was knocked down in two COAD cell lines to figure out its role in the glycolytic activity and malignant phenotype of cancer cells. Cancer cells were further injected into nude mice subcutaneously or via tail vein to evaluate tumor growth and metastasis. The downstream molecules involved were explored using bioinformatics tools, and the molecular interactions were confirmed by immunoprecipitation, luciferase assays, and rescue experiments. WTAP was abundantly expressed in COAD samples. Knockdown of WTAP suppressed glucose consumption, lactate production, and glycolysis, which consequently suppressed cancer cell growth and dissemination in vitro and in vivo. WTAP promoted m6A methylation and stabilized forkhead box P3 (FOXP3) mRNA with the participation of the m6A “reader” YTHDF1. FOXP3 could further bind to SMARCE1 promoter for transcriptional activation. Rescue experiments showed that upregulation of FOXP3 or SMARCE1 restored the glycolytic activity in COAD cells and augmented the growth and mobility of cells both in vitro and in vivo. This study demonstrates that WTAP grants glycolytic activity to COAD and promotes tumor malignant development via the m6A modification of FOXP3 mRNA and the upregulation of SMARCE1. Graphical Abstract