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

Research output: Contribution to journalArticle

38 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

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Colitis
Carcinogenesis
Inflammation
Dextran Sulfate
Neoplasms
Azoxymethane
Post Translational Protein Processing
Heterozygote
hexosaminidase C
Colon
Animal Models
Incidence

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Yang, Y. R., Kim, D. H., Seo, Y. K., Park, D., Jang, H. J., Choi, S. Y., ... 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
Yang, Yong Ryoul ; Kim, Dae Hyun ; Seo, Young Kyo ; Park, Dohyun ; Jang, Hyun Jun ; Choi, Soo Youn ; Lee, Yong Hwa ; Lee, Gyun Hui ; Nakajima, Kazuki ; Taniguchi, Naoyuki ; Kim, Jung Min ; Choi, Eun Jeong ; Moon, Hyo Youl ; Kim, Il Shin ; Choi, Jang Hyun ; Lee, Ho ; Ryu, Sung Ho ; Cocco, Lucio ; Suh, Pann Ghill. / Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling. In: Oncotarget. 2015 ; Vol. 6, No. 14. pp. 12529-12542.
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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.",
author = "Yang, {Yong Ryoul} and Kim, {Dae Hyun} and Seo, {Young Kyo} and Dohyun Park and Jang, {Hyun Jun} and Choi, {Soo Youn} and Lee, {Yong Hwa} and Lee, {Gyun Hui} and Kazuki Nakajima and Naoyuki Taniguchi and Kim, {Jung Min} and Choi, {Eun Jeong} and Moon, {Hyo Youl} and Kim, {Il Shin} and Choi, {Jang Hyun} and Ho Lee and Ryu, {Sung Ho} and Lucio Cocco and Suh, {Pann Ghill}",
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Yang, YR, Kim, DH, Seo, YK, Park, D, Jang, HJ, Choi, SY, Lee, YH, Lee, GH, Nakajima, K, Taniguchi, N, Kim, JM, Choi, EJ, Moon, HY, Kim, IS, Choi, JH, Lee, H, Ryu, SH, Cocco, L & Suh, PG 2015, 'Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling', Oncotarget, vol. 6, no. 14, pp. 12529-12542. https://doi.org/10.18632/oncotarget.3725

Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling. / Yang, Yong Ryoul; Kim, Dae Hyun; Seo, Young Kyo; Park, Dohyun; Jang, Hyun Jun; Choi, Soo Youn; Lee, Yong Hwa; Lee, Gyun Hui; Nakajima, Kazuki; Taniguchi, Naoyuki; Kim, Jung Min; Choi, Eun Jeong; Moon, Hyo Youl; Kim, Il Shin; Choi, Jang Hyun; Lee, Ho; Ryu, Sung Ho; Cocco, Lucio; Suh, Pann Ghill.

In: Oncotarget, Vol. 6, No. 14, 01.01.2015, p. 12529-12542.

Research output: Contribution to journalArticle

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T1 - Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling

AU - Yang, Yong Ryoul

AU - Kim, Dae Hyun

AU - Seo, Young Kyo

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AU - Jang, Hyun Jun

AU - Choi, Soo Youn

AU - Lee, Yong Hwa

AU - Lee, Gyun Hui

AU - Nakajima, Kazuki

AU - Taniguchi, Naoyuki

AU - Kim, Jung Min

AU - Choi, Eun Jeong

AU - Moon, Hyo Youl

AU - Kim, Il Shin

AU - Choi, Jang Hyun

AU - Lee, Ho

AU - Ryu, Sung Ho

AU - Cocco, Lucio

AU - Suh, Pann Ghill

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N2 - 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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