Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer

// Huiming Chen 1,2 , Shijuan Gao 1 , Jiandong Li 1 , Dong Liu 1 , Chunjie Sheng 1 , Chen Yao 1,2 , Wei Jiang 1 , Jiaoxiang Wu 1,2 , Shuai Chen 1,3 and Wenlin Huang 1,3,4 1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China 2 School of Life Sciences, Anhui University, Hefei 230039, China 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 4 The Key Laboratory of Tumor Targeted Medicine in Guangdong Province, Guangzhou Double Bio-product Inc., Guangzhou 510663, China Correspondence to: Wenlin Huang, email: // Shuai Chen, email: // Keywords : epigenetic cancer therapy, surface plasmon resonance, cell cycle, apoptosis, cell migration Received : December 18, 2014 Accepted : March 18, 2015 Published : April 12, 2015 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 ( K D = 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.