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, Pann Ghill Suh

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42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)12529-12542
Number of pages14
JournalOncotarget
Volume6
Issue number14
DOIs
Publication statusPublished - 01-01-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology

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    Yang, Y. R., Kim, D. H., Seo, Y. K., Park, D., Jang, H. J., Choi, S. Y., Lee, Y. H., Lee, G. H., Nakajima, K., Taniguchi, N., Kim, J. M., Choi, E. J., Moon, H. Y., Kim, I. S., Choi, J. H., Lee, H., Ryu, S. H., Cocco, L., & Suh, P. G. (2015). Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling. Oncotarget, 6(14), 12529-12542. https://doi.org/10.18632/oncotarget.3725