Institute 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.
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
Cancer Res. 2018 Apr 1;78(7):1643-1656. doi: 10.1158/0008-5472.CAN-17-2403. Epub 2018 Jan 26.
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-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. FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. .
DNA 甲基化已被确定为胃癌（GC）的一个标志。鉴定受 DNA 启动子甲基化抑制的基因对于深入了解胃癌的分子发病机制至关重要。通过全基因组甲基化研究，我们发现转录因子叉头框 F2（FOXF2）在胃癌中优先被甲基化。然后，我们研究了 FOXF2 在胃癌中的功能意义和临床意义。FOXF2 在胃癌细胞系和肿瘤组织中因启动子甲基化而沉默，与 mRNA 表达呈负相关。FOXF2 的异位表达抑制了胃癌细胞系的增殖、集落形成、G1/S 细胞周期转变，诱导了细胞凋亡，并抑制了裸鼠异种移植肿瘤的生长；FOXF2 的敲低则产生了相反的效果。FOXF2 通过诱导β-连环蛋白蛋白的泛素化和降解来抑制 Wnt 信号，而不依赖于 GSK-3β。FOXF2 直接结合 E3 连接酶干扰素调节因子 2 结合蛋白样（IRF2BPL）的启动子，并诱导其转录表达。IRF2BPL 反过来与 β-连环蛋白相互作用，增加其泛素化和降解。多变量 Cox 回归分析确定 FOXF2 高甲基化为早期胃癌患者预后不良的独立预后因素。总之，FOXF2 是胃癌发生中的一个关键肿瘤抑制因子，其甲基化状态是胃癌患者的独立预后因素。FOXF2 介导的 E3 连接酶 IRF2BPL 的上调驱动了β-连环蛋白在胃癌中的泛素化和降解，阻断了 Wnt 信号通路并抑制了肿瘤发生。
