Suppression of ELF4 in ulcerative colitis predisposes host to colorectal cancer.
Suppression of ELF4 in ulcerative colitis predisposes host to colorectal cancer.
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DOI：
10.1016/j.isci.2021.102169
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发表时间：
2021-03-19
期刊：
影响因子：
5.8
通讯作者：
You F
中科院分区：
文献类型：
--
作者：
Du H;Xia H;Liu T;Li Y;Liu J;Xie B;Chen J;Liu T;Cao L;Liu S;Li S;Wang P;Wang D;Zhang Z;Li Y;Guo X;Wu A;Li M;You F
溃疡性结肠炎（UC）是一种慢性炎症性肠病，以复发和缓解结肠黏膜炎症为特征。对于患有UC的患者，结肠癌的风险较高已被广泛认识。在这里，我们发现Elf4−/−小鼠在单独使用葡聚糖硫酸钠（DSS）治疗3个周期后发生结肠肿瘤。我们进一步发现，ELF4抑制在UC和dss诱导的小鼠模型中普遍存在，这种抑制是由启动子区域甲基化引起的。ELF4在PARP1的PARylation作用下，通过转录调控多种DNA损伤修复机制组件。无论在体内还是体外，ELF4缺乏都会导致更严重的DNA损伤。口服蒙脱石粉可以防止DSS诱导结肠炎模型中ELF4的减少，降低偶氮甲烷（AOM）和DSS诱导结肠炎相关癌症（CAC）期间结肠肿瘤发展的风险。这些数据提供了CAC启动的额外机制，支持了“肿瘤启动的表观遗传启动模型”。Elf4的表达在结肠炎和结肠炎相关癌（CAC）中均受到抑制。Elf4缺乏导致小鼠对结肠炎和CAC的超易感性增加，Elf4通过PARP1的PARylation促进DNA损伤修复，口服蒙脱土降低CAC发生的风险；分子生物学;转录组
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by relapsing and remitting colon mucosal inflammation. For patients suffering from UC, a higher risk of colon cancer has been widely recognized. Here, we found that Elf4−/− mice developed colon tumors with 3 cycles of dextran sulfate sodium salt (DSS) treatment alone. We further showed that ELF4 suppression was prevalent in both patients with UC and DSS-induced mice models, and this suppression was caused by promoter region methylation. ELF4, upon PARylation by PARP1, transcriptionally regulated multiple DNA damage repair machinery components. Consistently, ELF4 deficiency leads to more severe DNA damage both in vitro and in vivo. Oral administration of montmorillonite powder can prevent the reduction of ELF4 in DSS-induced colitis models and lower the risk of colon tumor development during azoxymethane (AOM) and DSS induced colitis-associated cancer (CAC). These data provided additional mechanism of CAC initiation and supported the “epigenetic priming model of tumor initiation”. Elf4 expression is suppressed in both colitis and colitis-associated cancer (CAC). Elf4 deficiency leads to increased hyper-susceptibility to colitis and CAC in mice Elf4 promotes DNA damage repair upon PARylation by PARP1 Oral administration of montmorillonite lowers risk of CAC development Biochemistry; Molecular Biology; Transcriptomics
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影响因子：
2.4
作者：
Bischoff SC;Barbara G;Buurman W;Ockhuizen T;Schulzke JD;Serino M;Tilg H;Watson A;Wells JM
通讯作者：
Wells JM
影响因子：
15.8
作者：
Heazlewood CK;Cook MC;Eri R;Price GR;Tauro SB;Taupin D;Thornton DJ;Png CW;Crockford TL;Cornall RJ;Adams R;Kato M;Nelms KA;Hong NA;Florin TH;Goodnow CC;McGuckin MA
通讯作者：
McGuckin MA
影响因子：
7.3
作者：
González, R;de Medina, FS;Zarzuelo, A
通讯作者：
Zarzuelo, A
影响因子：
4.4
作者：
Lee, Ping-Hsien;Puppi, Monica;Lacorazza, H. Daniel
通讯作者：
Lacorazza, H. Daniel
炎症和大肠癌：结肠炎相关的肿瘤。
影响因子：
9
作者：
Grivennikov, Sergei I.
通讯作者：
Grivennikov, Sergei I.