Helicobacter pylori decreases p27 expression through the delta opioid receptor-mediated inhibition of histone acetylation within the p27 promoter.
Helicobacter pylori decreases p27 expression through the delta opioid receptor-mediated inhibition of histone acetylation within the p27 promoter.
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DOI：
10.1016/j.canlet.2012.07.032
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发表时间：
2012-12-29
期刊：
影响因子：
9.7
通讯作者：
Kim, Sung Soo
中科院分区：
文献类型：
--
作者：
Byun, Sang Won;Chang, Young Jun;Chung, In Sik;Moss, Steven F.;Kim, Sung Soo
慢性幽门螺杆菌感染与胃肿瘤抑制蛋白p27的表达降低有关。由于p27基因的转录可能通过g蛋白偶联δ阿片受体（DOR）刺激介导的组蛋白乙酰化来调节表观遗传，因此我们研究了幽门螺杆菌是否调节DOR/组蛋白乙酰化/p27启动子途径。乙酰化组蛋白和p300 （p27启动子内的一种基因特异性组蛋白乙酰转移酶）的水平通过ChIP测定。Western blot和免疫组化检测磷酸化- dor的表达。构建生长曲线，观察BrdU掺入后细胞的增殖情况。与未感染AGS亲本细胞的p27 mRNA水平相比，急性幽门螺杆菌感染AGS胃上皮细胞和慢性幽门螺杆菌感染AGS来源的HS3C细胞中p27的低表达分别与p27 mRNA表达降低约20%和40%相关。幽门螺杆菌感染后的低p27 mRNA水平与p27启动子组蛋白H4乙酰化降低15%-60%相关。p300向p27启动子的募集也因幽门螺杆菌感染而明显减少。幽门螺杆菌感染使体外培养的细胞和体内幽门螺杆菌感染的人胃粘膜磷酸化dor表达降低。在HS3C细胞中，细胞p27水平与细胞增殖呈负相关。这些结果表明，幽门螺杆菌通过调节DOR从而抑制p27启动子的组蛋白乙酰化来降低p27的表达。这些发现将胃p27低表达水平与幽门螺杆菌感染相关的胃癌发生率增加联系起来。
Chronic Helicobacter pylori infection is associated with the decreased expression of the gastric tumour suppressor protein p27. Because transcription of the gene p27 may be regulated epigenetically through histone acetylation, which is mediated by G-protein coupled delta opioid receptor (DOR) stimulation, we examined whether H. pylori regulates the DOR/histone acetylation/p27 promoter pathway. The levels of acetylated histone and p300, a gene-specific histone acetyltransferase within the p27 promoter, were measured using ChIP assays. The expression of phospho-DOR was evaluated by Western blot and immunohistochemical analyses. Growth curves were constructed, and cell proliferation was assessed after BrdU incorporation. Low p27 expression in acutely H. pylori-infected AGS gastric epithelial cells and in chronically H. pylori-infected AGS-derived HS3C cells was associated with approximate 20% and 40% decreases in p27 mRNA expression, respectively, when compared to p27 mRNA levels in uninfected AGS parental cells. The low p27 mRNA levels following H. pylori infection were associated with a 15%–60% reduction in p27 promoter histone H4 acetylation. The recruitment of p300 to the p27 promoter was also markedly decreased by H. pylori infection. The expression of phospho-DOR was decreased by H. pylori infection in cell lines in vitro and in H. pylori-infected human gastric mucosa in vivo. The level of cellular p27 inversely correlated with cell proliferation in HS3C cells. These results demonstrate that H. pylori decreases p27 expression by modulating the DOR and thereby inhibiting histone acetylation of the p27 promoter. These findings link low gastric p27 expression levels with increased instances of gastric carcinogenesis associated with H. pylori infection.
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