The Inhibitory Effect of (-)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity.

Jie Sheng,Yuxin Wang,Weilin Shi,Jiangfa Qi,Wenlin Long,Yao Xu,Jinbiao Liu,Hui Guo

doi:10.3390/molecules24162899

Abstract

Epigenetic modifications are important mechanisms responsible for cancer progression. Accumulating data suggest that (−)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, may hamper carcinogenesis by targeting epigenetic alterations. We found that signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2 (SCUBE2), a tumor suppressor gene, was hypermethylated in breast tumors. However, it is unknown whether EGCG regulates SCUBE2 methylation, and the mechanisms remain undefined. This study was designed to investigate the effect of EGCG on SCUBE2 methylation in breast cancer cells. We reveal that EGCG possesses a significantly inhibitory effect on cell viability in a dose- and time-dependent manner and presents more effects than other catechins. EGCG treatment resulted in enhancement of the SCUBE2 gene, along with elevated E-cadherin and decreased vimentin expression, leading to significant suppression of cell migration and invasion. The inhibitory effect of EGCG on SCUBE2 knock-down cells was remarkably alleviated. Further study demonstrated that EGCG significantly decreased the SCUBE2 methylation status by reducing DNA methyltransferase (DNMT) expression and activity. In summary, this study reported for the first time that SCUBE2 methylation can be reversed by EGCG treatment, finally resulting in the inhibition of breast cancer progression. These results suggest the epigenetic role of EGCG and its potential implication in breast cancer therapy.

Highlights

Carcinogenesis is a multistage event consisting of initiation, promotion, progression, and malignant conversion phases
We initially investigated the effect of EGCG on the breast cancer cell growth and viability
In order to determine the pharmacological and biological characteristics of EGCG, the IC50 values were calculated in breast cancer cells

Summary

Introduction

Carcinogenesis is a multistage event consisting of initiation, promotion, progression, and malignant conversion phases. Burgeoning evidence has confirmed that the carcinogenesis process depends on heritable variability and on epigenetic modifications, which are correlated with the different genetic code profiles without sequence alterations [1,2]. DNA methylation is one of the epigenetic mechanisms that occurs most commonly with silencing of tumor suppressor genes (TSGs). The altered TSG expression subsequently leads to accumulated physiological changes, paving the way for tumorigenesis [3,4]. A previous study reported that many TSGs are inactivated during neoplastic initiation and progression due to the promoter hypermethylation [5]. To reduce methylated state of the TSGs represents an emerging perspective approach for cancer therapies

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