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Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation.

Wang N, Wang Z, Wang Y, Xie X, Shen J, Peng C, You J, Peng F, Tang H, Guan X, Chen J - Oncotarget (2015)

Bottom Line: In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase.Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1.Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.

ABSTRACT
Breast cancer stem cells (CSCs) are considered as the root of mammary tumorigenesis. Previous studies have demonstrated that ISL efficiently limited the activities of breast CSCs. However, the cancer prevention activities of ISL and its precise molecular mechanisms remain largely unknown. Here, we report a novel function of ISL as a natural demethylation agent targeting WIF1 to prevent breast cancer. ISL administration suppressed in vivo breast cancer initiation and progression, accompanied by reduced CSC-like populations. A global gene expression profile assay further identified WIF1 as the main response gene of ISL treatment, accompanied by the simultaneous downregulation of β-catenin signaling and G0/G1 phase arrest in breast CSCs. In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase. Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1. Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

No MeSH data available.


Related in: MedlinePlus

The molecular binding mode of ISL with the catalytic domain within DNMT1It was predicted by the LigandFit algorithm in Discovery Studio 2.5 using the homology-docking template of 3SWR. It was found that ISL could form stable hydrogen bonds with four active residues including GLU1168, GLU1266, ARG1312 and ASN1578. Meanwhile, ISL could also form a strong π–π interaction with TRP1170. Blue dashed lines, hydrogen bonds; orange line, π–π interactions.
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Figure 9: The molecular binding mode of ISL with the catalytic domain within DNMT1It was predicted by the LigandFit algorithm in Discovery Studio 2.5 using the homology-docking template of 3SWR. It was found that ISL could form stable hydrogen bonds with four active residues including GLU1168, GLU1266, ARG1312 and ASN1578. Meanwhile, ISL could also form a strong π–π interaction with TRP1170. Blue dashed lines, hydrogen bonds; orange line, π–π interactions.

Mentions: To further explore the binding mode of ISL with DNMT1 at the molecular level, we conducted a molecular docking analysis of ISL using a homology model 3SWR at the catalytic site of the DNMT1 crystal structure. Using Discovery studio software, we determined that ISL could stably be found at the C-terminal catalytic domain of the catalytic site of DNMT1. In particular, ISL could form stable hydrogen bonds with four active residues including GLU1168, GLU1266, ARG1312 and ASN1578. ISL could also form a strong π–π interactions with TRP1170, which were crucial to the catalytic mechanism of DNMT1 (Figure 9).


Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation.

Wang N, Wang Z, Wang Y, Xie X, Shen J, Peng C, You J, Peng F, Tang H, Guan X, Chen J - Oncotarget (2015)

The molecular binding mode of ISL with the catalytic domain within DNMT1It was predicted by the LigandFit algorithm in Discovery Studio 2.5 using the homology-docking template of 3SWR. It was found that ISL could form stable hydrogen bonds with four active residues including GLU1168, GLU1266, ARG1312 and ASN1578. Meanwhile, ISL could also form a strong π–π interaction with TRP1170. Blue dashed lines, hydrogen bonds; orange line, π–π interactions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496402&req=5

Figure 9: The molecular binding mode of ISL with the catalytic domain within DNMT1It was predicted by the LigandFit algorithm in Discovery Studio 2.5 using the homology-docking template of 3SWR. It was found that ISL could form stable hydrogen bonds with four active residues including GLU1168, GLU1266, ARG1312 and ASN1578. Meanwhile, ISL could also form a strong π–π interaction with TRP1170. Blue dashed lines, hydrogen bonds; orange line, π–π interactions.
Mentions: To further explore the binding mode of ISL with DNMT1 at the molecular level, we conducted a molecular docking analysis of ISL using a homology model 3SWR at the catalytic site of the DNMT1 crystal structure. Using Discovery studio software, we determined that ISL could stably be found at the C-terminal catalytic domain of the catalytic site of DNMT1. In particular, ISL could form stable hydrogen bonds with four active residues including GLU1168, GLU1266, ARG1312 and ASN1578. ISL could also form a strong π–π interactions with TRP1170, which were crucial to the catalytic mechanism of DNMT1 (Figure 9).

Bottom Line: In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase.Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1.Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.

ABSTRACT
Breast cancer stem cells (CSCs) are considered as the root of mammary tumorigenesis. Previous studies have demonstrated that ISL efficiently limited the activities of breast CSCs. However, the cancer prevention activities of ISL and its precise molecular mechanisms remain largely unknown. Here, we report a novel function of ISL as a natural demethylation agent targeting WIF1 to prevent breast cancer. ISL administration suppressed in vivo breast cancer initiation and progression, accompanied by reduced CSC-like populations. A global gene expression profile assay further identified WIF1 as the main response gene of ISL treatment, accompanied by the simultaneous downregulation of β-catenin signaling and G0/G1 phase arrest in breast CSCs. In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase. Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1. Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

No MeSH data available.


Related in: MedlinePlus