A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells
A Novel Plant Homeodomain Finger 10–Mediated Antiapoptotic Mechanism Involving Repression of Caspase-3 in Gastric Cancer Cells
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DOI：
10.1158/1535-7163.mct-09-1162
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发表时间：
2010-06
影响因子：
5.7
通讯作者：
M. Wei;Bing-ya Liu;Liping Su;Jian-fang Li;Jun Zhang;Yingyan Yu;M. Yan;Zhong-Yin Yang;Xue-hua Chen;Jia-yun Liu;X. Lv;Hui Nie;Qing Zhang;Zhong Zheng;Beiqin Yu;J. Ji;Jia-nian Zhang;Zhenggang Zhu;Q. Gu
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文献类型：
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作者：
M. Wei;Bing-ya Liu;Liping Su;Jian-fang Li;Jun Zhang;Yingyan Yu;M. Yan;Zhong-Yin Yang;Xue-hua Chen;Jia-yun Liu;X. Lv;Hui Nie;Qing Zhang;Zhong Zheng;Beiqin Yu;J. Ji;Jia-nian Zhang;Zhenggang Zhu;Q. Gu
胃癌的发生机制一直是研究的热点。目前，植物同源结构域（PHD）指（PHF）蛋白已涉及肿瘤抑制和进展。然而，PHF 10的功能尚未得到很好的表征。在这里，我们表明，不同水平的PHF 10蛋白在胃癌细胞系中观察到。PHF 10表达的改变与肿瘤细胞的生长有关，在体内外均可导致胃癌细胞凋亡。在胃癌细胞中PHF 10表达的敲低导致在RNA和蛋白水平上显著诱导caspase-3表达，从而以时间依赖性方式诱导caspase-3底物的改变。此外，荧光素酶分析的结果表明，PHF 10作为一个转录阻遏物时，PHF 10中包含的两个PHD结构域是完整的。结合以前的研究结果，我们的数据表明，PHF 10转录调节caspase-3的表达。最后，通过使用系统性报告基因缺失和染色质免疫沉淀分析，我们定位了caspase-3启动子中核苷酸-270和-170之间的区域，该区域是PHF 10有效抑制caspase-3启动子活性所必需的。总的来说，我们的研究结果表明，PHF 10抑制caspase-3的表达，并在转录水平上损害了人胃癌细胞的程序性死亡途径。Mol Cancer Ther; 9（6）; 1764-74。©2010 AACR。
The mechanisms governing tumorigenesis of gastric cancer have been an area of intense investigation. Currently, plant homeodomain (PHD) finger (PHF) proteins have been implicated in both tumor suppression and progression. However, the function of PHF10 has not been well characterized. Here, we show that various levels of PHF10 protein were observed in gastric cancer cell lines. Alteration of PHF10 expression, which is associated with tumor cell growth, may result in apoptosis in gastric cancer cells both in vitro and in vivo. Knockdown of PHF10 expression in gastric cancer cells led to significant induction of caspase-3 expression at both the RNA and protein levels and thus induced alteration of caspase-3 substrates in a time-dependent manner. Moreover, results from luciferase assays indicated that PHF10 acted as a transcriptional repressor when the two PHD domains contained in PHF10 were intact. Combined with previous findings, our data suggest that PHF10 transcriptionally regulates the expression of caspase-3. Finally, by using systematic reporter deletion and chromatin immunoprecipitation assays, we localized a region between nucleotides −270 and −170 in the caspase-3 promoter that was required for the efficient inhibition of caspase-3 promoter activity by PHF10. Collectively, our findings show that PHF10 repressed caspase-3 expression and impaired the programmed cell death pathway in human gastric cancer at the transcriptional level. Mol Cancer Ther; 9(6); 1764–74. ©2010 AACR.