OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice

Y R Yang; H-J Jang; S Yoon; Y H Lee; D Nam; I S Kim; H Lee; H Kim; J H Choi; B H Kang; S H Ryu; P-G Suh

doi:10.1038/oncsis.2014.24

OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice

Oncogenesis. 2014 Jul 7;3(7):e109. doi: 10.1038/oncsis.2014.24.

Authors

Y R Yang¹, H-J Jang², S Yoon¹, Y H Lee¹, D Nam¹, I S Kim¹, H Lee³, H Kim⁴, J H Choi¹, B H Kang¹, S H Ryu⁵, P-G Suh¹

Affiliations

¹ School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
² 1] School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea [2] Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk.
³ Research Institute, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
⁴ Department of Pathology and Yonsei University College of Medicine, Seoul, Republic of Korea.
⁵ Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk.

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.