title: Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer.
abstract: Polycomb repressive complex 2 (PRC2), which is responsible for the trimethylation of H3K27 (H3K27me3), plays a part in tumorigenesis, development and/or maintenance of adult tissue specificity. The pivotal role of PRC2 in cancer makes it a therapeutic target for epigenetic cancer therapy. However, natural compounds targeting the enhancer of zeste homolog 2 (EZH2) - embryonic ectoderm development (EED) interaction to disable PRC2 complex are scarcely reported. Here, we reported the screening and identification of natural compounds which could disrupt the EZH2-EED interaction. One of these compounds, wedelolactone, binds to EED with a high affinity (KD = 2.82 μM), blocks the EZH2-EED interaction in vitro, induces the degradation of PRC2 core components and modulates the expression of detected PRC2 downstream targets and cancer-related genes. Furthermore, some PRC2-dependent cancer cells undergone growth arrest upon treatment with wedelolactone. Thus, wedelolactone and its derivatives which target the EZH2-EED interaction could be candidates for the treatment of PRC2-dependent cancer.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|School of Life Sciences, Anhui University, Hefei 230039, China.
authors.forename: Huiming
authors.initials: H
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shijuan
authors.initials: S
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Chunjie
authors.initials: C
authors.lastname: Sheng
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|School of Life Sciences, Anhui University, Hefei 230039, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|School of Life Sciences, Anhui University, Hefei 230039, China.
authors.forename: Jiaoxiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.|The Key Laboratory of Tumor Targeted Medicine in Guangdong Province, Guangzhou Double Bio-product Inc., Guangzhou 510663, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D003374:Coumarins; C491488:EED protein, human; C051122:wedelolactone; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: apoptosis; cell cycle; cell migration; epigenetic cancer therapy; surface plasmon resonance