O-GlcNAcylation-mediated regulation of FOXM1 expression through its ubiquitination in a human gastric adenocarcinoma cell line, NUGC-3

Abstract

O-GlcNAcylation is a dynamic post-translational modification of cytonuclear molecules and regulated by only two enzymes, OGT and OGA, which add and remove a glucose metabolite, UDP-GlcNAc, respectively. Previously, we reported that augmented O-GlcNAcylation increased the expression of FOXM1, which is an oncogenic transcription factor and overexpressed in various cancers, by reducing its ubiquitination (Ub). Here, we examined the O-GlcNAcylation-mediated regulation of FOXM1 expression through FBXL2 E3 ligase and USP22 deubiquitinase. FOXM1 Ub was regulated by the two enzymes and, interestingly, FBXL2 itself was ubiquitinated, which was promoted by an OGA inhibitor (Thiamet G, TMG) treatment, accompanying with elevated FBXL2 O-GlcNAcylation. Moreover, FBXL2 induction using the Tet-on system showed that FOXM1 expression and cell proliferation were reduced, while those were attenuated by TMG treatment or USP22 induction in NUGC-3 cells. These data suggest that elevated O-GlcNAcylation might contribute to FOXM1 overexpression by regulating its Ub in various cancers. Because FOXM1 or USP22 was reported not only to be elevated in the various clinical cancers but also to be involved in drug resistance. So now, we are going to evaluate the combination treatment of anticancer drugs with the inhibitor of FOXM1 or OGT in NUGC-3 cells.