Forkhead box F2 suppresses gastric cancer through a novel FOXF2–IRF2BPL–b-Catenin signaling axis

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G ₁ –S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing b-catenin protein ubiquitination and degradation independently of GSK-3b. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with b-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients. Significance: FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of b-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis.