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

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.
Authors	Neng Wang, Zhiyu Wang, Yu Wang, Xiaoming Xie, Jiangang Shen, Cheng Peng, Jieshu You, Fu Peng, Hailin Tang, Xinyuan Guan, Jianping Chen
Journal	Oncotarget (Oncotarget) Vol. 6 Issue 12 Pg. 9854-76 ( 2015) ISSN: 1949-2553 [Electronic] United States
PMID	25918249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Anticarcinogenic Agents Chalcones Extracellular Matrix Proteins Intercellular Signaling Peptides and Proteins RNA, Small Interfering Wif1 protein, mouse beta Catenin isoliquiritigenin
Topics	Adaptor Proteins, Signal Transducing Animals Anticarcinogenic Agents (chemistry) Breast Neoplasms (metabolism) Catalytic Domain Cell Line, Tumor Chalcones (chemistry) DNA Methylation (drug effects) Dietary Supplements Epigenesis, Genetic Extracellular Matrix Proteins (metabolism) Female Gene Expression Regulation, Neoplastic Gene Silencing Humans Intercellular Signaling Peptides and Proteins (metabolism) Lung Neoplasms (prevention & control, secondary) MCF-7 Cells Mammary Neoplasms, Experimental (prevention & control) Mice Mice, Transgenic Molecular Docking Simulation Neoplasm Metastasis Neoplastic Stem Cells (cytology, drug effects) Promoter Regions, Genetic RNA, Small Interfering (metabolism) Signal Transduction beta Catenin (metabolism)

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