Guo Zijun, He Lingnan, Wang Weijun, Tian Shuxin, Lin Rong
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, Shanghai, China.
Cancer Lett. 2025 Jun 1;619:217643. doi: 10.1016/j.canlet.2025.217643. Epub 2025 Mar 18.
Fucosyltransferase 2 (FUT2) is an enzyme that adds fucose to proteins or lipids via α-1,2-fucosylation in the intestinal mucosa. While FUT2 deficiency is linked to increased susceptibility to inflammatory bowel disease (IBD), its role in colorectal cancer (CRC) is unclear, and the molecular mechanisms involved remain largely unknown. We established an azoxymethane (AOM) and dextran sulfate sodium (DSS) model to induce CRC. FUT2 expression was assessed in human CRC tissues, AOM/DSS-induced mouse models, and CRC cell lines using qRT-PCR, western blotting, and UEA-I staining. FUT2 knockout (FUT2) mice were treated with AOM/DSS, and FUT2-overexpressing CRC cells were created to evaluate the effects of FUT2 on apoptosis in both in vitro and in vivo settings through Western blot analyses and functional assays. N-glycoproteomics, UEA-I chromatography, and co-immunoprecipitation were utilized to identify regulatory mechanisms and target fucosylated proteins. FUT2 expression and α-1,2-fucosylation were significantly decreased in CRC. FUT2 deficiency worsened AOM/DSS-induced CRC and reduced tumor apoptosis, while FUT2 overexpression induced apoptosis and inhibited proliferation in CRC cells and xenografts. Mechanistically, FUT2 appears to suppress autophagy by impairing lysosomal function and directly targeting and fucosylating LAMP1, contributing to lysosomal dysfunction. Our study reveals a fucosylation-dependent antitumor mechanism of FUT2 in CRC, suggesting potential therapeutic strategies for CRC treatment.
岩藻糖基转移酶2（FUT2）是一种通过在肠黏膜中进行α-1,2-岩藻糖基化作用将岩藻糖添加到蛋白质或脂质上的酶。虽然FUT2缺陷与炎症性肠病（IBD）易感性增加有关，但其在结直肠癌（CRC）中的作用尚不清楚，所涉及的分子机制也大多未知。我们建立了一种用氧化偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）诱导结直肠癌的模型。使用qRT-PCR、蛋白质印迹法和荆豆凝集素I（UEA-I）染色在人结直肠癌组织、AOM/DSS诱导的小鼠模型和结直肠癌细胞系中评估FUT2的表达。用AOM/DSS处理FUT2基因敲除（FUT2 -/-）小鼠，并构建FUT2过表达的结直肠癌细胞，通过蛋白质印迹分析和功能试验评估FUT2在体外和体内环境中对细胞凋亡的影响。利用N-糖蛋白质组学、UEA-I色谱法和免疫共沉淀来确定调控机制并鉴定岩藻糖基化靶蛋白。在结直肠癌中，FUT2的表达和α-1,2-岩藻糖基化显著降低。FUT2缺陷使AOM/DSS诱导的结直肠癌恶化并减少肿瘤细胞凋亡，而FUT2过表达则诱导结直肠癌细胞和异种移植瘤中的细胞凋亡并抑制增殖。从机制上讲，FUT2似乎通过损害溶酶体功能并直接靶向LAMP1并使其岩藻糖基化，从而抑制自噬，导致溶酶体功能障碍。我们的研究揭示了FUT2在结直肠癌中一种依赖岩藻糖基化的抗肿瘤机制，为结直肠癌治疗提示了潜在的治疗策略。
