TY - JOUR
T1 - Genistein modulates signaling pathways and targets several epigenetic markers in hela cells
AU - Sundaram, Madhumitha Kedhari
AU - Unni, Sreepoorna
AU - Somvanshi, Pallavi
AU - Bhardwaj, Tulika
AU - Mandal, Raju K.
AU - Hussain, Arif
AU - Haque, Shafiul
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - Cancer
KW - Epigenetic
KW - Genistein
KW - Tumour suppressor gene
UR - https://www.scopus.com/pages/publications/85075376972
U2 - 10.3390/genes10120955
DO - 10.3390/genes10120955
M3 - Artículo
C2 - 31766427
AN - SCOPUS:85075376972
SN - 2073-4425
VL - 10
JO - Genes
JF - Genes
IS - 12
M1 - 955
ER -
