Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling.
Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling.
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DOI：
10.18632/oncotarget.3725
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Suh PG
中科院分区：
文献类型：
--
作者：
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
o - glcn酰化是一种可逆的翻译后修饰。O-GlcNAc的添加和去除分别由O-GlcNAc转移酶（OGT）和O-GlcNAcase （OGA）催化。最近的证据表明，o - glcn酰化的调节在炎症性疾病和肿瘤发生中很重要。在本研究中，我们发现在葡聚糖硫酸钠（DSS）诱导的结肠炎和偶氮氧甲烷(AOM)/DSS诱导的结肠炎相关癌（CAC）动物模型的结肠组织中o - glcnac酰化水平升高。此外，与匹配的正常组织相比，人CAC组织中的o - glcnac酰化水平升高。为了研究o - glcn酰化在结肠炎中的功能作用，我们使用了o - glcn酰化水平升高的OGA杂合子小鼠。OGA+/−小鼠对dss诱导的结肠炎的易感性高于OGA+/+小鼠。OGA+/−小鼠结肠肿瘤的发生率高于OGA+/+小鼠。在分子研究中，升高的O-GlcNAc水平被证明通过增加RelA/p65与其靶启动子的结合来增强NF-κB信号的激活。我们还发现p65- o - glcn酰化位点的Thr-322和Thr352对p65启动子结合至关重要。这些结果表明，结肠组织中o - glcnac酰化水平的升高通过破坏NF-κ b依赖性转录活性的调节，促进了结肠炎和CAC的发生。
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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影响因子：
29.4
作者：
Asquith MJ;Boulard O;Powrie F;Maloy KJ
通讯作者：
Maloy KJ
DOI：
10.1152/ajpgi.00328.2004
发表时间：
2005-05-01
影响因子：
4.5
作者：
Fukata, M;Michelsen, KS;Abreu, MT
通讯作者：
Abreu, MT
影响因子：
4.4
作者：
Karrasch, Thomas;Kim, Joo-Sung;Jobin, Christian
通讯作者：
Jobin, Christian
影响因子：
16.6
作者：
Hart GW;Slawson C;Ramirez-Correa G;Lagerlof O
通讯作者：
Lagerlof O
DOI：
10.1073/pnas.0813210106
发表时间：
2009-03-03
影响因子：
11.1
作者：
Kawauchi, Keiko;Araki, Keigo;Tanaka, Nobuyuki
通讯作者：
Tanaka, Nobuyuki