Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-{beta}-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 GC. Using genome-wide methylation studies we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in GC. We then investigated the functional significance and clinical implication of FOXF2 in GC. FOXF2 was silenced in GC cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1-S cell cycle transition, induced apoptosis of GC cell lines and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. 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 β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early stage GC patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for GC patients.

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