Emerging evidence suggests that aberrant O-GlcNAcylation is associated with
tumorigenesis. Many oncogenic factors are O-GlcNAcylated, which modulates their functions. However, it remains unclear how O-GlcNAcylation and O-GlcNAc cycling
enzymes,
O-GlcNAc transferase (OGT) and
O-GlcNAcase (OGA), affect the development of
cancer in animal models. In this study, we show that reduced level of OGA attenuates colorectal
tumorigenesis induced by
Adenomatous polyposis coli (Apc) mutation. The levels of O-GlcNAcylation and O-GlcNAc cycling
enzymes were simultaneously upregulated in intestinal
adenomas from mice, and in human patients. In two independent microarray data sets, the expression of OGA and OGT was significantly associated with poor
cancer-specific survival of
colorectal cancer (CRC) patients. In addition, OGA heterozygosity, which results in increased levels of O-GlcNAcylation, attenuated intestinal
tumor formation in the Apc(min/+) background. Apc(min/+) OGA(+/-) mice exhibited a significantly increased survival rate compared with Apc(min/+) mice. Consistent with this, Apc(min/+) OGA(+/-) mice expressed lower levels of Wnt target genes than Apc(min/+). However, the knockout of OGA did not affect Wnt/β-
catenin signaling. Overall, these findings suggest that OGA is crucial for
tumor growth in CRC independently of Wnt/β-
catenin signaling.