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Sulforaphane Reverses the Expression of Various Tumor Suppressor Genes by Targeting DNMT3B and HDAC1 in Human Cervical Cancer Cells.

Ali Khan M, Kedhari Sundaram M, Hamza A, Quraishi U, Gunasekera D, Ramesh L, Goala P, Al Alami U, Ansari MZ, Rizvi TA, Sharma C, Hussain A - Evid Based Complement Alternat Med (2015)

Bottom Line: 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.Thus, SFN may have significant implications for epigenetic based therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Natural Science and Public Health, College of Sustainability Sciences & Humanities, Zayed University, P.O. Box 19282, Dubai, UAE.

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.

No MeSH data available.


Related in: MedlinePlus

Predicted interaction between ligands (SFN and 5-Aza-dC) with mDNMT3B. The mDNMT3B is depicted in ribbon representation showing docked models of SFN in red and 5-Aza-dC in blue and the residues defining the pocket as light blue. Inset focuses on the binding pocket shown in orange. Active site C-651 and cofactor binding E-605 are labeled and shown in purple solid bonds.
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fig4: Predicted interaction between ligands (SFN and 5-Aza-dC) with mDNMT3B. The mDNMT3B is depicted in ribbon representation showing docked models of SFN in red and 5-Aza-dC in blue and the residues defining the pocket as light blue. Inset focuses on the binding pocket shown in orange. Active site C-651 and cofactor binding E-605 are labeled and shown in purple solid bonds.

Mentions: The docking results produced 49 clusters of the ligand SFN around the modelled catalytic domain of DNMT3B. Analysis of these clusters showed that 31 of these 49 clusters bind in the substrate binding cavity as defined by CASTp. These clusters together contained a total of 188 elements out of 256 predicted binding modes. Interestingly, the top 9 clusters (from 0 to 8) containing a total of 86 elements were in this cavity. Table 3 shows the summary result of SwissDock docking with the FullFitness and estimated ΔG values for the most favorable interaction. Observation of the majority of the clusters, including the top ranked ones in the cavity, strongly suggests that the preferred binding of SFN on mDNMT3B is within the substrate binding cavity and overlaps with binding site of 5-Aza-dC. Figure 4 shows the visualization of the most energetically favorable binding of SFN and 5-Aza-dC on the protein mDNMT3B. Table 4 lists all the mDNMT3B residues within 5 Å of the most energetically favorable docked model of SFN.


Sulforaphane Reverses the Expression of Various Tumor Suppressor Genes by Targeting DNMT3B and HDAC1 in Human Cervical Cancer Cells.

Ali Khan M, Kedhari Sundaram M, Hamza A, Quraishi U, Gunasekera D, Ramesh L, Goala P, Al Alami U, Ansari MZ, Rizvi TA, Sharma C, Hussain A - Evid Based Complement Alternat Med (2015)

Predicted interaction between ligands (SFN and 5-Aza-dC) with mDNMT3B. The mDNMT3B is depicted in ribbon representation showing docked models of SFN in red and 5-Aza-dC in blue and the residues defining the pocket as light blue. Inset focuses on the binding pocket shown in orange. Active site C-651 and cofactor binding E-605 are labeled and shown in purple solid bonds.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4487331&req=5

fig4: Predicted interaction between ligands (SFN and 5-Aza-dC) with mDNMT3B. The mDNMT3B is depicted in ribbon representation showing docked models of SFN in red and 5-Aza-dC in blue and the residues defining the pocket as light blue. Inset focuses on the binding pocket shown in orange. Active site C-651 and cofactor binding E-605 are labeled and shown in purple solid bonds.
Mentions: The docking results produced 49 clusters of the ligand SFN around the modelled catalytic domain of DNMT3B. Analysis of these clusters showed that 31 of these 49 clusters bind in the substrate binding cavity as defined by CASTp. These clusters together contained a total of 188 elements out of 256 predicted binding modes. Interestingly, the top 9 clusters (from 0 to 8) containing a total of 86 elements were in this cavity. Table 3 shows the summary result of SwissDock docking with the FullFitness and estimated ΔG values for the most favorable interaction. Observation of the majority of the clusters, including the top ranked ones in the cavity, strongly suggests that the preferred binding of SFN on mDNMT3B is within the substrate binding cavity and overlaps with binding site of 5-Aza-dC. Figure 4 shows the visualization of the most energetically favorable binding of SFN and 5-Aza-dC on the protein mDNMT3B. Table 4 lists all the mDNMT3B residues within 5 Å of the most energetically favorable docked model of SFN.

Bottom Line: 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.Thus, SFN may have significant implications for epigenetic based therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Natural Science and Public Health, College of Sustainability Sciences & Humanities, Zayed University, P.O. Box 19282, Dubai, UAE.

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.

No MeSH data available.


Related in: MedlinePlus