The synergistic function of long and short forms of ?4GalT1 in p53-mediated drug resistance in bladder cancer cells.

?1,4-galactosyltransferase-1 (?4GalT1) is a type II membrane protein that catalyzes the transfer of galactose (Gal) from UDP-Gal to N-acetylglucosamine (GlcNAc) and forms a LacNAc structure. ?4GalT1 has a long form (termed ?4GalT1-L) and a short form (termed ?4GalT1-S) in mammalian cells. Although ?4GalT1 has been proven to play an important ...
role in many biological and pathological processes, such as differentiation, immune responses and cancer development, the different functions of the two ?4GalT1 forms remain ambiguous. In this study, we demonstrated that total ?4GalT1 was upregulated in bladder cancer. Overexpression of ?4GalT1-S, but not ?4GalT1-L, increased drug resistance in bladder epithelial cells by upregulating p53 expression. Glycoproteomic analysis revealed that the substrate specificities of the two ?4GalT1 forms were different. Among the LacNAcylated proteins, the E3 ligase MDM2 could be preferentially modified by ?4GalT1-L compared to ?4GalT1-S, and this modification could increase the binding of MDM2 and p53 and further facilitate the degradation of p53. Our data proved that the two forms of ?4GalT1 could synergistically regulate p53-mediated cell survival under chemotherapy treatment. These results provide insights into the role of ?4GalT1-L and ?4GalT1-S and suggest their differentially important implications in the development of bladder cancer.
Mesh Terms:
Animals, Epithelial Cells, Mammals, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Urinary Bladder, Urinary Bladder Neoplasms
Biochim Biophys Acta Mol Cell Res
Date: Feb. 01, 2023
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