Epigallocatechin Gallate Inhibits Colon Cancer Cell Proliferation By Modulating Epigenetic Enzymes (Dnmts, Hdacs, And Hats)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit antioxidant and antitumorigenic properties using in vitro and in vivo models of colon cancer and in small cohort studies of colorectal cancer patients. The development of colon cancer is influenced by both genetic and epigenetic factors, with increased risk associated with age, lifestyle, and environmental exposures. Thus, parsing the interactions of genetic components and epigenetic modulators of gene expression in colon cancer development and progression is essential. The mechanism by which EGCG exerts antitumorigenic activity against colon cancer has not been completely elucidated. This study investigates potential mechanism(s) by which EGCG inhibits proliferation of HCT-116 and HT-29 colon cancer cell lines, via epigenetic pathways. Briefly, HCT-116 and HT-29 cells were treated with EGCG (5-150 µM) and control drugs: 5-FU (50-200 µg/mL), 5-AZA (5 µM), SAHA (1-10 µM), and anacardic acid (10 µM) for 48-72 h. Cell proliferation (MTT), cell cycle and apoptosis (PI-FC and TUNEL), enzyme activity, gene and protein expression were measured. EGCG inhibited proliferation of HCT-116 and HT-29 by promoting S-phase cell cycle arrest and apoptosis. Expression and global enzyme activity of DNMTs (1, 3a, 3b), HDACs (1-4), and HATs (P300, PCAF, P400) were differentially expressed in both cell lines. A consistent upregulation of DNMT3b and downregulation of HDAC3 in both cell lines were observed. Global and gene-specific regulation of DNA methylation and histone acetylation by EGCG is under current study in our lab. The antiproliferative effects of EGCG can potentially be attributed to restoring normal global and gene-specific methylation/acetylation pattern in colon cancer cells by regulating DNMTs, HDACs, and HATs. This study provides evidence for the utilization of EGCG as a potential chemopreventive agent against colon cancer. Furthermore, identifying mechanisms by which EGCG overrides tumor-driven genetic deregulation to inhibit carcinogenesis expands our knowledge on pathways contributing to colon cancer and plausible targets for epigenetic therapy/prevention. This project is supported by NIH: RO1CA96694 and P30CA054174. Citation Format: April B. Cabang, Yuan Fang, Jay Morris, Michael J. Wargovich. Epigallocatechin gallate inhibits colon cancer cell proliferation by modulating epigenetic enzymes (DNMTs, HDACs, and HATs). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2014-410