Oncotarget

Research Papers:

The inhibitory activity of gallic acid against DNA methylation: application of gallic acid on epigenetic therapy of human cancers

Yui-Ping Weng, Pin-Feng Hung, Wen-Yen Ku, Chang-Yuan Chang, Bo-Han Wu, Ming-Han Wu, Jau-Ying Yao, Ji-Rui Yang and Chia-Huei Lee _

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Oncotarget. 2018; 9:361-374. https://doi.org/10.18632/oncotarget.23015

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Abstract

Yui-Ping Weng1, Pin-Feng Hung2, Wen-Yen Ku1, Chang-Yuan Chang1, Bo-Han Wu1, Ming-Han Wu1, Jau-Ying Yao2, Ji-Rui Yang2 and Chia-Huei Lee2

1Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan

2National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan

Correspondence to:

Chia-Huei Lee, email: [email protected]

Keywords: gallic acid; DNA methyltransferase; chemoprevention; epigenetics; post-fermentation oolong tea extract

Received: July 11, 2017     Accepted: November 13, 2017     Published: December 07, 2017

ABSTRACT

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, Aspergillus sojae 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.


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