Weng Yui-Ping, Hung Pin-Feng, Ku Wen-Yen, Chang Chang-Yuan, Wu Bo-Han, Wu Ming-Han, Yao Jau-Ying, Yang Ji-Rui, Lee Chia-Huei
Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan.
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
Oncotarget. 2017 Dec 7;9(1):361-374. doi: 10.18632/oncotarget.23015. eCollection 2018 Jan 2.
Epigenome aberrations have been observed in tobacco-associated human malignancies. (-)-epigallocatechin-3-gallate (EGCG) has been proven to modulate gene expression by targeting DNA methyltransferases (DNMTs) through a proposed mechanism involving the gallate moiety of EGCG. We show that gallic acid (GA) changes the methylome of lung cancer and pre-malignant oral cell lines and markedly reduces both nuclear and cytoplasmic DNMT1 and DNMT3B within 1 week. GA exhibits stronger cytotoxicity against the lung cancer cell line H1299 than EGCG. We found that GA reactivates the growth arrest and DNA damage-inducible 45 (GADD45) signaling pathway may through the demethylation of CCNE2 and CCNB1 in H1299 cells. To improve the epigenetic anti-cancer activities of oolong tea, we identified a fungus, which can efficiently increase the GA content in oolong tea via a 2-week fermentation process. The fungus dramatically increased GA up to 44.8 fold in the post-fermentation oolong tea extract (PFOTE), resulting in enhanced demethylation effects and a significant reduction in the nuclear abundances of DNMT1, DNMT3A, and DNMT3B in lung cancer cell lines. PFOTE also showed stronger anti-proliferation activities than oolong tea extract (OTE) and increased sensitivity to cisplatin in H1299 cells. In summary, we demonstrate the potent inhibitory effects of GA on the activities of DNMTs and provide a strong scientific foundation for the use of specialized fermented oolong tea high in GA as an effective dietary intervention strategy for tobacco-associated cancers.
在与烟草相关的人类恶性肿瘤中已观察到表观基因组异常。（-）-表没食子儿茶素-3-没食子酸酯（EGCG）已被证明可通过一种涉及EGCG没食子酸部分的机制靶向DNA甲基转移酶（DNMTs）来调节基因表达。我们发现没食子酸（GA）可改变肺癌和癌前口腔细胞系的甲基化组，并在1周内显著降低细胞核和细胞质中的DNMT1和DNMT3B。GA对肺癌细胞系H1299的细胞毒性比EGCG更强。我们发现GA可能通过H1299细胞中CCNE2和CCNB1的去甲基化作用重新激活生长停滞和DNA损伤诱导蛋白45（GADD45）信号通路。为了提高乌龙茶的表观遗传抗癌活性，我们鉴定出一种真菌，它可以通过为期2周的发酵过程有效提高乌龙茶中的GA含量。这种真菌使发酵后乌龙茶提取物（PFOTE）中的GA显著增加高达44.8倍，从而增强了去甲基化作用，并显著降低了肺癌细胞系中DNMT1、DNMT3A和DNMT3B的细胞核丰度。PFOTE在H1299细胞中还表现出比乌龙茶提取物（OTE）更强的抗增殖活性，并增加了对顺铂的敏感性。总之，我们证明了GA对DNMTs活性具有强大的抑制作用，并为使用富含GA的特殊发酵乌龙茶作为与烟草相关癌症的有效饮食干预策略提供了坚实的科学基础。
