Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2
| Autor: | Wenxuan Zhen, Fan Yang, Jie-Bo Lin, Shan-He Yu, Xiao-Jian Sun, Yi-Fan Wang, Dan Wang, Chih-Hung Hsu, Yu-Han Wu, Yi Zhou, Peng-Fei Xu, Yi Wang, Li-Ping Shu, Ying Huang, Tao Cheng, Yi Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Chromatin Immunoprecipitation
Myeloid Methyltransferase Tanshinone I H3K27me3 Medicine (miscellaneous) Salvia miltiorrhiza Animals Genetically Modified Histones Cell Line Tumor medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Enhancer of Zeste Homolog 2 Protein EZH2 RNA-Seq Pharmacology Toxicology and Pharmaceutics (miscellaneous) Zebrafish Cell Proliferation Leukemia biology Chemistry Gene Expression Profiling Polycomb Repressive Complex 2 Myeloid leukemia Gene signature Surface Plasmon Resonance medicine.disease biology.organism_classification Antineoplastic Agents Phytogenic Xenograft Model Antitumor Assays hematopoiesis Neoplasm Proteins Gene Expression Regulation Neoplastic medicine.anatomical_structure Matrix Metalloproteinase 9 Abietanes Cancer research Transcriptome Research Paper Protein Binding |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases. |
| Databáze: | OpenAIRE |
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