The Role And Molecular Mechanism Of FUT2 In Regulation Of Colon Cancer Progression

Objective:Fucosyltransferase 2(FUT2)is one of the enzymes responsible for the addition of fucose to proteins or lipids by α-1,2-fucosylation on the intestinal mucosa.Intestinal epithelium-specific FUT2 deficiency increases susceptibility to IBD,which have two-to three times increased risk of developing colon cancer compared with healthy subject.Colon cancer is still a major cause of cancer-related death.However,the underlying molecular mechanism of FUT2 and colon cancer remains unknown.Methods:Intestinal epithelium-specific FUT2 knockout(Fut2ΔIEC)mice were generated,as were wild type(WT)mice.The AOM/DSS-induced colitis-associated cancer(CAC)mouse model was established,and quantitative sequencing of N-glycosylated protein modifications was performed.Lentivirus was used to overexpress FUT2.The expression of FUT2 in human colon cancer tissues,tumor tissues of CAC WT mice,and colon cancer cell lines was assessed by qRT-PCR,western blotting,and Ulex europaeus agglutinin-I(UEA-I)staining.Next,the effects of FUT2 on proliferation and apoptosis in CAC were evaluated by western blot and functional assays in vitro and in vivo.Colon cancer cells with FUT2 stably overexpressed were used to establish a xenograft model.In addition,chloroquine(CQ)was introduced to determine the role of autophagy in FUT2-related tumor progression.Ultimately,co-immunoprecipitation and UEA chromatography were used to confirm the α-1,2-fucosylation between FUT2 and lysosome associated membrane protein-1(LAMP1).Western blotting,GFP-mRFP-LC3 staining and functional assays were performed to explore the mechanism of FUT2.Results:We found that FUT2 was decreased in colon cancer.We observed that FUT2 promotes tumor apoptosis and inhibits tumor proliferation through suppression of autophagy,a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions.Furthermore,we demonstrated that FUT2 inhibits tumor growth and promotes tumor apotosis in a xenograft model of colon cancer.FUT2 caused impaired autophagic degradation in vitro,a crucial process in autophagy,by disturbing the function of lysosomes and contributing to autophagosome accumulation.We found FUT2 directly regulates α-1,2-fucosylation of LAMP 1 in colon cancer.Furthermore,FUT2 caused lysosomal dysfunction by directly interacting with LAMP1,and knockdown of LAMP 1 reversed the antitumor effects of FUT2 in colon cancer.Conclusions:These findings suggest that FUT2 exerts an antitumor effect on autophagy-related proliferation in colon cancer by directly regulating α-1,2-fucosylati on of LAMP 1.Herein,we describe a novel mechanism of FUT2 that suppresses the progression of colon cancer.FUT2-LAMP1-autophagy might be the promising target for the treatment and prognostication of colon cancer.