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.
Highlights
Cancer is a major public health problem in the world
ectoderm development (EED) was reported to bind the N-terminal sequence of enhancer of zeste homolog 2 (EZH2) [20], so natural compounds which could bind to EED might disrupts the EZH2-EED interaction
We performed competitive coimmunoprecipitation experiments to identify EED-EZH2 disruptors among natural compounds with response unit (RU) higher than 50
Summary
Cancer is a major public health problem in the world. In the United States, estimated new cancer cases and cancer deaths in 2014 are 1,665,540 and 585,720, respectively [1]. Polycomb group (PcG) proteins, conserved chromatin proteins, are widely deployed in higher eukaryotes to implement gene silencing [5]. PcG proteins mainly function by forming two evolutionarily conserved multimeric protein complexes, Polycomb repressive complexes 1 (PRC1) and Polycomb repressive complexes 2 (PRC2). They are involved in monoubiquitylation of lysine 119 of histone H2A (H2AK119ub) and di- and tri-methylation of lysine 27 of histone H3 (H3K27me3), respectively [11]. PRC2 contains three essential subunits: a catalytic subunit with www.impactjournals.com/oncotarget methyltransferase activity, enhancer of zeste homolog 2 (EZH2) and two noncatalytic subunits, suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). Much attention is paid to their association with sorts of cancers like colon cancer, breast cancer, leukemia, hepatocellular carcinoma and tongue cancer [12,13,14,15]
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