Abstract
Sulforaphane (SFN) may hinder carcinogenesis by altering epigenetic events in the cells; however, its molecular mechanisms are unclear. The present study investigates the role of SFN in modifying epigenetic events in human cervical cancer cells, HeLa. HeLa cells were treated with SFN (2.5 µM) for a period of 0, 24, 48, and 72 hours for all experiments. After treatment, expressions of DNMT3B, HDAC1, RARβ, CDH1, DAPK1, and GSTP1 were studied using RT-PCR while promoter DNA methylation of tumor suppressor genes (TSGs) was studied using MS-PCR. Inhibition assays of DNA methyl transferases (DNMTs) and histone deacetylases (HDACs) were performed at varying time points. Molecular modeling and docking studies were performed to explore the possible interaction of SFN with HDAC1 and DNMT3B. Time-dependent exposure to SFN decreases the expression of DNMT3B and HDAC1 and significantly reduces the enzymatic activity of DNMTs and HDACs. Molecular modeling data suggests that SFN may interact directly with DNMT3B and HDAC1 which may explain the inhibitory action of SFN. Interestingly, time-dependent reactivation of the studied TSGs via reversal of methylation in SFN treated cells correlates well with its impact on the epigenetic alterations accumulated during cancer development. Thus, SFN may have significant implications for epigenetic based therapy.
Highlights
Genetic alterations, such as mutations and aberrant epigenetic regulation, lead to susceptibility to develop cancer [1, 2]
DNA methyltransferase (DNMT) activity assay was performed in nuclear extract, extracted from SFN treated HeLa cells at various time points (24, 48, and 72 h)
Whether the activity of DNMT correlated with the expression of DNMT3B induced by SFN treatment in HeLa cells was determined
Summary
Genetic alterations, such as mutations and aberrant epigenetic regulation, lead to susceptibility to develop cancer [1, 2]. Evidence-Based Complementary and Alternative Medicine methylation and histone modification, via key targeting enzymes, namely, DNA methyltransferases and histone deacetylases, are under clinical studies [8,9,10]. Certain disadvantages such as lack of specificity, short duration of action, and unpredicted effects on functional and structural patterns of normal cells restrict the general use of these synthetic epigenetic drugs [8,9,10]. Research on plant derived dietary factors is gaining more attention to utilize them as epigenetic modifiers since these agents have been found to revert the aberrant epigenetic patterns with the least undesirable traits which are caused by available synthetic epigenetic drugs
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