The synergistic function of long and short forms of 84GalT1 in p53-mediated drug resistance in bladder cancer cells

81,4-galactosyltransferase-1 (84GalT1) 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. 84GalT1 has a long form (termed 84GalT1-L) and a short form (termed 84GalT1-S) in mammalian cells. Although 84GalT1 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 84GalT1 forms remain ambiguous. In this study, we demonstrated that total 84GalT1 was upregulated in bladder cancer. Overexpression of 84GalT1-S, but not 84GalT1-L, increased drug resistance in bladder epithelial cells by upregulating p53 expression. Glycoproteomic analysis revealed that the substrate specificities of the two 84GalT1 forms were different. Among the LacNA-cylated proteins, the E3 ligase MDM2 could be preferentially modified by 84GalT1-L compared to 84GalT1-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 84GalT1 could synergistically regulate p53-mediated cell survival under chemotherapy treatment. These results provide insights into the role of 84GalT1-L and 84GalT1-S and suggest their differentially important implications in the development of bladder cancer.