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FUT2-Dependent Fucosylation of LAMP1 Promotes Apoptosis of Colorectal Cancer Cells by Regulating Autophagy-Lysosomal Pathway
56 Pages Posted: 22 Mar 2024
More...Abstract
Background: FUT2 is one of the enzymes responsible for adding fucose to proteins or lipids by α-1,2-fucosylation on the intestinal mucosa. However, the underlying molecular mechanism of FUT2 in colorectal cancer (CRC) remains unknown.
Methods: The AOM and DSS model was established to induced CRC. The expression of FUT2 in human CRC tissues, AOM/DSS-induced CRC mice, and CRC cell lines by qRT-PCR, western blotting, and UEA-I staining. Intestinal epithelium-specific FUT2 knockout (FUT2△IEC) mice incubated with AOM/DSS, FUT2-overexpressed CRC cells, and xenograft model were established. The effects of FUT2 on apoptosis in CRC were evaluated by western blot and functional assays in vitro and in vivo. N-glycoproteomics, UEA-I chromatography, and co-IP were monitored to dissect the regulatory mechanism and identify the target fucosylated protein.
Findings: FUT2 expression and α-1,2-fucosylation decrease in CRC. Intestinal epithelium-specific FUT2 deficiency exacerbates AOM/DSS-induced CRC and reduces tumor apoptosis. Contrarily, FUT2 promotes tumor apoptosis and inhibits tumor proliferation in CRC cell lines and xenograft model. FUT2-mediated CRC apoptosis could be concerned with the suppression of autophagy. FUT2 caused impaired autophagic degradation in vitro by disturbing the function of lysosomes and contributing to autophagosome accumulation. FUT2 directly targets LAMP1, regulates α-1,2-fucosylation of LAMP1, and leads to lysosomal dysfunction. LAMP1 α-1,2-fucosylation is involved in FUT2-mediated inhibition of autophagy and antitumor effects.
Interpretation: Our study highlights a fucosylation-dependent antitumor mechanism of CRC, which may provide a fascinating therapeutic strategy for treating CRC.
Funding: This work was supported by the National Natural Science Foundation of China (Nos. 81974068 and 82203341).
Declaration of Interest: All authors declare that they have no conflict of interest.
Ethical Approval: Informed consent was obtained from each patient prior to endoscopy and biopsy, and ethical approval for using human subjects was obtained from the Institutional Review Board of Tongji Medical College, Huazhong University of Science and Technology. All the animal procedures were performed in accordance with the ‘Guide for the Care and Use of Laboratory Animals’ published by the National Institutes of Health, approved by the ethics committee for experimental research, Tongji Medical College, Huazhong University of Science and Technology.
Keywords: FUT2, fucosylation, autophagy, lysosome, LAMP1, colorectal cancer
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