Volume 120, Issue 10 p. 18357-18369
RESEARCH ARTICLE

Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells

Madhumitha Kedhari Sundaram

Madhumitha Kedhari Sundaram

School of Life Sciences, Manipal Academy of Higher Education, Dubai, United Arab Emirates

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Arif Hussain

Corresponding Author

Arif Hussain

School of Life Sciences, Manipal Academy of Higher Education, Dubai, United Arab Emirates

Correspondence Arif Hussain, School of Life Sciences, Manipal Academy of Higher Education, 345050 Dubai, United Arab Emirates. Email: [email protected]

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Shafiul Haque

Shafiul Haque

Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia

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Ritu Raina

Ritu Raina

School of Life Sciences, Manipal Academy of Higher Education, Dubai, United Arab Emirates

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Nazia Afroze

Nazia Afroze

School of Life Sciences, Manipal Academy of Higher Education, Dubai, United Arab Emirates

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First published: 06 June 2019
Citations: 75

Abstract

The central role of epigenomic alterations in carcinogenesis has been widely acknowledged, particularly the impact of DNA methylation on gene expression across all stages of carcinogenesis is considered vital for both diagnostic and therapeutic strategies. Dietary phytochemicals hold great promise as safe anticancer agents and effective epigenetic modulators. This study was designed to investigate the potential of a phytochemical, quercetin as a modulator of the epigenetic pathways for anticancer strategies. Biochemical activity of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and global genomic DNA methylation was quantitated by an enzyme-linked immunosorbent assay based assay in quercetin-treated HeLa cells. Molecular docking studies were performed to predict the interaction of quercetin with DNMTs and HDACs. Quantitative methylation array was used to assess quercetin-mediated alterations in the promoter methylation of selected tumor suppressor genes (TSGs). Quercetin induced modulation of chromatin modifiers including DNMTs, HDACs, histone acetyltransferases (HAT) and HMTs, and TSGs were assessed by quantitative reverse transcription PCR (qRT-PCR). It was found that quercetin modulates the expression of various chromatin modifiers and decreases the activity of DNMTs, HDACs, and HMTs in a dose-dependent manner. Molecular docking results suggest that quercetin could function as a competitive inhibitor by interacting with residues in the catalytic cavity of several DNMTs and HDACs. Quercetin downregulated global DNA methylation levels in a dose- and time-dependent manner. The tested TSGs showed steep dose-dependent decline in promoter methylation with the restoration of their expression. Our study provides an understanding of the quercetin's mechanism of action and will aid in its development as a candidate for epigenetic-based anticancer therapy.

CONFLICT OF INTERESTS

The authors declare that there is no conflict of interests.

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