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Centchroman altered the expressions of tumor‐related genes through active chromatin modifications in mammary cancer
Author(s) -
Khan Sajid,
Shukla Samriddhi,
Sinha Sonam,
Meeran Syed Musthapa
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22424
Subject(s) - biology , telomerase reverse transcriptase , cancer research , dna methylation , dnmt1 , epigenetics , methyltransferase , cancer , breast cancer , chromatin , telomerase , histone , microbiology and biotechnology , methylation , gene expression , gene , genetics
Centchroman (CC), a female oral contraceptive, has been shown to possess breast anti‐cancer activities. Recently, we have shown CC‐mediated antimetastatic effect through reversal of epithelial‐to‐mesenchymal transition (EMT) in breast cancer. The loss of tumor suppressor genes (TSGs) has been shown to promote EMT in breast cancer. Therefore, in the present study, we investigated the effect of CC‐treatment on the expression of tumor‐related genes including both tumor suppressor‐ and tumor promoter genes in breast cancer. CC treatment resulted in G 0 /G 1 phase cell cycle arrest in human breast cancer MDA‐MB‐231, SK‐BR‐3, and ZR‐75‐1 cells with the concomitant induction of TSGs such as p21 WAF1/CIP1 , p16 INK4a , and p27 Kip1 . In addition, CC treatment also resulted in the downregulation of tumor promoter gene, human telomerase reverse transcriptase ( hTERT ). The induction of TSGs and downregulation of hTERT was found to be correlated with decreased expression levels of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Further, mechanistic studies revealed CC‐induced global DNA demethylation and alterations in the enrichment of chromatin modification markers at the promoters of p21 and hTERT . These in vitro results were corroborated with in vivo findings in 4T1‐syngeneic mouse model, where CC‐treatment resulted in tumor growth reduction accompanied with the induction of TSGs and alterations in the expression levels of HDACs, DNMT1, and histone modification markers. Overall, our findings suggest that CC‐treatment induces the expression of TSGs and downregulates hTERT through histone modifications and DNA methylation changes. Therefore, CC could be further developed into a promising drug candidate against breast cancer. © 2015 Wiley Periodicals, Inc.