Oncotarget

Research Papers:

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

Yong Ryoul Yang, Dae Hyun Kim, Young-Kyo Seo, Dohyun Park, Hyun-Jun Jang, Soo Youn Choi, Yong Hwa Lee, Gyun Hui Lee, Kazuki Nakajima, Naoyuki Taniguchi, Jung-Min Kim, Eun-Jeong Choi, Hyo Youl Moon, Il Shin Kim, Jang Hyun Choi, Ho Lee, Sung Ho Ryu, Lucio Cocco and Pann-Ghill Suh _

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Oncotarget. 2015; 6:12529-12542. https://doi.org/10.18632/oncotarget.3725

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Abstract

Yong Ryoul Yang1, Dae Hyun Kim1, Young-Kyo Seo1, Dohyun Park2, Hyun-Jun Jang1,2, Soo Youn Choi1, Yong Hwa Lee1, Gyun Hui Lee1, Kazuki Nakajima3, Naoyuki Taniguchi3, Jung-Min Kim1, Eun-Jeong Choi2, Hyo Youl Moon1, Il Shin Kim1, Jang Hyun Choi1, Ho Lee4, Sung Ho Ryu2, Lucio Cocco5 and Pann-Ghill Suh1

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.


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