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Forkhead Box F2 Suppresses Gastric Cancer through a Novel FOXF2-IRF2BPL-β-Catenin Signaling Axis
Akira Higashimori1,2, Yujuan Dong1,3, Yanquan Zhang1
1Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease and Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong.
Abstract:
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, G1-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 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 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 β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. Cancer Res; 78(7); 1643-56. ©2018 AACR.
Insights
Forkhead box F2 (FOXF2) is silenced by DNA methylation in gastric cancer, acting as a tumor suppressor. Its methylation predicts poor survival, highlighting its role in gastric carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- DNA methylation is a key mechanism in gastric cancer (GC) development.
- Identifying epigenetically silenced genes offers insights into GC pathogenesis.
Purpose of the Study:
- Investigate the role of forkhead box F2 (FOXF2) in gastric cancer.
- Determine the clinical significance of FOXF2 methylation in GC patients.
Main Methods:
- Genome-wide methylation analysis to identify methylated genes in GC.
- In vitro studies (cell lines) and in vivo studies (xenografts) to assess FOXF2 function.
- Analysis of Wnt signaling pathway components and E3 ligase interactions.
- Multivariate Cox regression for prognostic analysis.
Main Results:
- FOXF2 is frequently methylated and silenced in GC, inversely correlating with mRNA expression.
- FOXF2 suppresses GC cell proliferation, promotes apoptosis, and inhibits tumor growth.
- FOXF2 inhibits Wnt signaling by promoting β-catenin degradation via IRF2BPL.
- FOXF2 hypermethylation is an independent predictor of poor survival in early-stage GC.
Conclusions:
- FOXF2 functions as a tumor suppressor in gastric carcinogenesis.
- FOXF2 methylation serves as a prognostic biomarker for gastric cancer patients.
- The FOXF2-IRF2BPL-β-catenin axis is crucial for suppressing Wnt signaling in GC.
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