Research Papers:

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

Neng Wang, Zhiyu Wang, Yu Wang, Xiaoming Xie, Jiangang Shen, Cheng Peng, Jieshu You, Fu Peng, Hailin Tang, Xinyuan Guan and Jianping Chen _

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Oncotarget. 2015; 6:9854-9876. https://doi.org/10.18632/oncotarget.3396

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Neng Wang1,*, Zhiyu Wang1,2,*, Yu Wang3, Xiaoming Xie4, Jiangang Shen1, Cheng Peng5, Jieshu You1, Fu Peng1, Hailin Tang4, Xinyuan Guan6, Jianping Chen1,5

1School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong

2Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangdong, China

3Department of Pharmacology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong

4Department of Breast Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

5School of Pharmaceutical Science, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, China

6Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong

*These authors have contributed equally to this work

Correspondence to:

Jianping Chen, e-mail: [email protected]

Keywords: mammary tumorigenesis, cancer stem cells, WIF1 demethylation, DNMT1, Isoliquiritigenin

Received: December 25, 2014     Accepted: February 15, 2015     Published: March 26, 2015


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.

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