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Open AccessArticle

Genistein Modulates Signaling Pathways and Targets Several Epigenetic Markers in HeLa Cells

1
School of Life Sciences, Manipal Academy of Higher Education, P.O. Box 345050 Dubai, United Arab Emirates
2
Department of Life and Environmental Sciences, College of Natural and Health Sciences, Zayed University, P.O. Box 19282 Dubai, United Arab Emirates
3
Department of Biotechnology, TERI School of Advanced Studies, 10, Institutional Area, Vasant Kunj, New Delhi-110070, India
4
Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan-45142, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Genes 2019, 10(12), 955; https://doi.org/10.3390/genes10120955
Received: 30 September 2019 / Revised: 8 November 2019 / Accepted: 11 November 2019 / Published: 21 November 2019
(This article belongs to the Special Issue The Role of Genotoxicity in Infertility and Cancer Development)
Background: Several epigenetic changes are responsible for transcriptional alterations of signaling pathways and tumour suppressor genes (TSGs) contributing to carcinogenesis. This study was aimed to examine the effect of the phytochemical, genistein on various molecular targets in HeLa cells. Methods: Quantitative PCR was used to analyze the expression of various molecular targets. Biochemical assays were employed to study the epigenetic enzymes. To correlate the transcriptional status of the selected TSGs and epigenetic modulation, their promoter 5’CpG methylation levels were evaluated by quantitative methylation array followed by methylation specific restriction digestion. Results: The expression of several genes involved in the cell cycle regulation, migration, inflammation, phosphatidylinositol 3-kinase (PI3K) and mitogen activated kinase-like protein (MAPK) pathway were found to be modulated including CCNB1, TWIST1, MMP14, TERT, AKT1, PTPRR, FOS and IL1A. Genistein modulated the expression of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), demethylases, and histone phosphorylases. Furthermore, genistein decreased the activity of DNMTs, HDACs, and HMTs and reduced global DNA methylation levels. Promoter methylation of several TSGs, including FHIT, RUNX3, CDH1, PTEN, and SOC51, was lowered with corresponding transcriptional increase. Network analysis indicated similar effect of genistein. Conclusion: This study presents a comprehensive mechanism of action of genistein showcasing effective epigenetic modulation and widespread transcriptional changes resulting in restoration of tumour suppressor gene expression. This study corroborates the development of genistein as a candidate for anti-cancer therapy.
Keywords: genistein; epigenetic; tumour suppressor gene; cancer genistein; epigenetic; tumour suppressor gene; cancer
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Sundaram, M.K.; Unni, S.; Somvanshi, P.; Bhardwaj, T.; Mandal, R.K.; Hussain, A.; Haque, S. Genistein Modulates Signaling Pathways and Targets Several Epigenetic Markers in HeLa Cells. Genes 2019, 10, 955.

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