Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling.
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.
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Yong Ryoul
YR
Yang
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Dae Hyun
DH
Kim
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Young-Kyo
YK
Seo
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
Dohyun
D
Park
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.|Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
Hyun-Jun
HJ
Jang
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Soo Youn
SY
Choi
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Yong Hwa
YH
Lee
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Gyun Hui
GH
Lee
Disease Glycomics Team, Systems Glycobiology Research Group, RIKENMax Planck Joint Research Center, Global Research Cluster, RIKEN, Hirosawa, Wako, Saitama, Japan.
Kazuki
K
Nakajima
Disease Glycomics Team, Systems Glycobiology Research Group, RIKENMax Planck Joint Research Center, Global Research Cluster, RIKEN, Hirosawa, Wako, Saitama, Japan.
Naoyuki
N
Taniguchi
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Jung-Min
JM
Kim
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
Eun-Jeong
EJ
Choi
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Hyo Youl
HY
Moon
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Il Shin
IS
Kim
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Jang Hyun
JH
Choi
Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Ho
H
Lee
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
Sung Ho
SH
Ryu
Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Lucio
L
Cocco
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Pann-Ghill
PG
Suh
D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
D016328:NF-kappa B; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases
O-GlcNAcase; O-GlcNAcylation; colitis; colitis-associated cancer