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Published on: October 6, 2014
OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice
1School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Abstract:
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.
Insights
Reduced O-GlcNAcase (OGA) levels attenuate colorectal cancer growth by decreasing O-GlcNAcylation, independent of Wnt/β-catenin signaling. This finding highlights OGA as a potential therapeutic target for colorectal cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aberrant O-GlcNAcylation is linked to cancer development.
- The roles of O-GlcNAc cycling enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), in tumorigenesis are not fully understood.
- O-GlcNAcylation modulates the function of many oncogenic factors.
Purpose of the Study:
- To investigate the impact of O-GlcNAc cycling enzymes, specifically OGA, on colorectal cancer development in animal models.
- To determine the relationship between OGA expression, O-GlcNAcylation levels, and patient survival in colorectal cancer (CRC).
Main Methods:
- Utilized Apc(min/+) mouse models with altered OGA levels.
- Analyzed O-GlcNAcylation and OGA/OGT expression in mouse intestinal adenomas and human CRC samples.
- Examined gene expression of Wnt target genes and Wnt/β-catenin signaling pathway activity.
Main Results:
- Reduced OGA levels attenuated colorectal tumorigenesis in Apc(min/+) mice.
- Increased O-GlcNAcylation and OGA/OGT expression were observed in intestinal adenomas and correlated with poor CRC patient survival.
- OGA heterozygosity in Apc(min/+) mice led to increased survival and reduced Wnt target gene expression, but did not affect Wnt/β-catenin signaling.
Conclusions:
- OGA plays a critical role in colorectal cancer growth.
- OGA's pro-tumorigenic function in CRC appears to be independent of the Wnt/β-catenin signaling pathway.
- Targeting OGA may represent a novel therapeutic strategy for colorectal cancer.
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