Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation.
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.
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Neng
N
Wang
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.|Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangdong, China.
Zhiyu
Z
Wang
Department of Pharmacology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Yu
Y
Wang
Department 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.
Xiaoming
X
Xie
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Jiangang
J
Shen
School of Pharmaceutical Science, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, China.
Cheng
C
Peng
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Jieshu
J
You
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Fu
F
Peng
Department 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.
Hailin
H
Tang
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Xinyuan
X
Guan
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.|School of Pharmaceutical Science, Chengdu University of Traditional Chinese Medicine, Sichuan, Chengdu, China.
Jianping
J
Chen
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry*; D001943:Breast Neoplasms / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D047188:Chalcones / Q000737:chemistry*; D019175:DNA Methylation / Q000187:drug effects*; D019587:Dietary Supplements; D044127:Epigenesis, Genetic; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016588:Anticarcinogenic Agents; D047188:Chalcones; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C118544:Wif1 protein, mouse; D051176:beta Catenin; C040920:isoliquiritigenin
DNMT1; Isoliquiritigenin; WIF1 demethylation; cancer stem cells; mammary tumorigenesis