(-)-Epigallocatechin-3-gallate induces cancer cell apoptosis via acetylation of amyloid precursor protein
(-)-Epigallocatechin-3-gallate induces cancer cell apoptosis via acetylation of amyloid precursor protein
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(-)-Epigallocatechin-3-gallate 通过淀粉样前体蛋白的乙酰化诱导癌细胞凋亡。
DOI：
10.1007/s12032-014-0390-0
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发表时间：
2015-01-01
期刊：
影响因子：
3.4
通讯作者：
Fang, Shuhuan
中科院分区：
文献类型：
--
作者：
Hu, Qian;Chang, Xiang;Fang, Shuhuan
表观遗传修饰参与癌症发病机制，HDACis被认为是潜在的治疗药物。我们和其他人已经显示了EGCG对HDAC 1的抑制活性。但是关于表观遗传调节在癌症中的作用知之甚少。在这里，我们试图证明，EGCG作为HDACi下调APP的表达，这是病理生理上调癌症和发挥关键作用的癌细胞生长。我们使用PC-12细胞、SK-N-SH细胞和原发性肿瘤组织进行分析。将4周龄雄性无胸腺裸鼠用于异位肿瘤生长测定。我们采用Western blotting分析检测了Bcl-2、Bax、APP、caspase-3、caspase-7、HDAC 1和H4 Ac。采用AnnexinV-FITC和TUNEL染色检测细胞凋亡。免疫组化染色观察肿瘤组织。我们证明了EGCG抑制异种移植肾上腺嗜铬细胞瘤的生长。流式细胞仪分析和TUNEL染色显示，EGCG诱导细胞凋亡。用EGCG处理导致Bcl-2减少，但Bax和活化的caspase-3和caspase-7增加。免疫荧光显示HDAC抑制剂EGCG导致组蛋白H4高度乙酰化。免疫荧光染色和Western blot分析显示，EGCG降低APP水平。HDAC 1特异性沉默导致caspase-3和caspase-7活化和切割。我们的研究结果首次证实了EGCG和APP在抑制肿瘤生长方面的功能性相互作用，并提供了EGCG抗肿瘤的新的表观遗传学效应。
Epigenetic modifications are involved in cancer pathogenesis, and HDACis are considered potential therapeutic agents. We and others have shown the inhibitory activity of EGCG on HDAC1. But little is known about the effect of EGCG as on epigenetic regulation in cancer. Here, we try to demonstrate that EGCG acts as an HDACi downregulated APP expression, which was pathophysiologically upregulated in cancers and exerts a key role in cancer cell growth. We used PC-12 cells, SK-N-SH cells and primary tumor tissues for our analysis. Male 4-week-old athymic nude mice were used for heterotopic tumor growth assay. We employed Western blotting analysis to detect Bcl-2, Bax, APP, caspase-3, caspase-7, HDAC1 and H4Ac. We used AnnexinV-FITC and TUNEL staining for apoptosis detection. Tumor tissueswere examined by immunohistochemical staining. We demonstrated that EGCG suppresses the growth of xenografted adrenal pheochromocytoma. Flowcytometry analysis and TUNEL staining showed that EGCG induced the apoptosis. Treatment with EGCG resulted in decrease in Bcl-2 but increase in Bax and activated caspase-3 and caspase-7. HDAC inhibitor EGCG leaded to hyperacetylated histone H4 by immunofluorescence. EGCG decreased APP levels by immunofluorescence staining and Western blot analysis. Silencing specific to HDAC1 leaded to caspase-3 and caspase-7 activation and cleavage. Our results are the first to demonstrate a functional interaction between EGCG and APP in suppression tumor growth, and provide a new epigenetic effects of EGCG on antitumor.