Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling

// Yong Ryoul Yang 1 , Dae Hyun Kim 1 , Young-Kyo Seo 1 , Dohyun Park 2 , Hyun-Jun Jang 1,2 , Soo Youn Choi 1 , Yong Hwa Lee 1 , Gyun Hui Lee 1 , Kazuki Nakajima 3 , Naoyuki Taniguchi 3 , Jung-Min Kim 1 , Eun-Jeong Choi 2 , Hyo Youl Moon 1 , Il Shin Kim 1 , Jang Hyun Choi 1 , Ho Lee 4 , Sung Ho Ryu 2 , Lucio Cocco 5 and Pann-Ghill Suh 1 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, Republic of Korea 3 Disease Glycomics Team, Systems Glycobiology Research Group, RIKENMax Planck Joint Research Center, Global Research Cluster, RIKEN, Hirosawa, Wako, Saitama, Japan 4 Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea 5 Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy Correspondence to: Pann-Ghill Suh, email: // Keywords : O-GlcNAcylation, O-GlcNAcase, colitis, colitis-associated cancer Received : May 06, 2014 Accepted : March 11, 2015 Published : March 30, 2015 Abstract O-GlcNAcylation is a reversible post-translational modification. O-GlcNAc addition and removal is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. More recent evidence indicates that regulation of O-GlcNAcylation is important for inflammatory diseases and tumorigenesis. In this study, we revealed that O-GlcNAcylation was increased in the colonic tissues of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) animal models. Moreover, the O-GlcNAcylation level was elevated in human CAC tissues compared with matched normal counterparts. To investigate the functional role of O-GlcNAcylation in colitis, we used OGA heterozygote mice, which have an increased level of O-GlcNAcylation. OGA +/- mice have higher susceptibility to DSS-induced colitis than OGA +/+ mice. OGA +/- mice exhibited a higher incidence of colon tumors than OGA +/+ mice. In molecular studies, elevated O-GlcNAc levels were shown to enhance the activation of NF-κB signaling through increasing the binding of RelA/p65 to its target promoters. We also found that Thr-322 and Thr352 in the p65-O-GlcNAcylation sites are critical for p65 promoter binding. These results suggest that the elevated O-GlcNAcylation level in colonic tissues contributes to the development of colitis and CAC by disrupting regulation of NF-κB-dependent transcriptional activity.