PUBLICATION

Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2

Authors
Huang, Y., Yu, S.H., Zhen, W.X., Cheng, T., Wang, D., Lin, J.B., Wu, Y.H., Wang, Y.F., Chen, Y., Shu, L.P., Wang, Y., Sun, X.J., Zhou, Y., Yang, F., Hsu, C.H., Xu, P.F.
ID
ZDB-PUB-210608-14
Date
2021
Source
Theranostics   11: 6891-6904 (Journal)
Registered Authors
Sun, Xiao-Jian
Keywords
EZH2, H3K27me3, Tanshinone I, hematopoiesis, leukemia
Datasets
GEO:GSE155573, GEO:GSE155574
MeSH Terms
  • Hematopoiesis/drug effects*
  • Hematopoiesis/genetics
  • Humans
  • Leukemia/drug therapy*
  • Leukemia/enzymology
  • Leukemia/genetics
  • Leukemia/metabolism*
  • Zebrafish
  • ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism*
  • Surface Plasmon Resonance
  • Abietanes/pharmacology*
  • Polycomb Repressive Complex 2/metabolism
  • Antineoplastic Agents, Phytogenic/pharmacology*
  • Matrix Metalloproteinase 9/genetics
  • Matrix Metalloproteinase 9/metabolism*
  • Transcriptome/genetics
  • Protein Binding
  • Salvia miltiorrhiza/chemistry
  • Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors*
  • Enhancer of Zeste Homolog 2 Protein/genetics
  • Enhancer of Zeste Homolog 2 Protein/metabolism
  • RNA-Seq
  • Neoplasm Proteins/genetics
  • Neoplasm Proteins/metabolism*
  • Animals
  • Animals, Genetically Modified
  • Xenograft Model Antitumor Assays
  • Chromatin Immunoprecipitation
  • Gene Expression Profiling
  • Cell Proliferation/drug effects
  • Cell Proliferation/genetics
  • Gene Expression Regulation, Neoplastic/drug effects
  • Gene Expression Regulation, Neoplastic/genetics
  • Cell Line, Tumor
  • Histones/metabolism
(all 36)
PubMed
34093860 Full text @ Theranostics
Abstract
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hkz4
    		Point Mutation
    rj1TgTransgenic Insertion
      y1TgTransgenic Insertion
        zf169TgTransgenic Insertion
          zf3053TgTransgenic Insertion
            1 - 5 of 5
            Show
            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            abcg2bMO1-abcg2bMRPHLNO
            mmp9MO4-mmp9MRPHLNO
            1 - 2 of 2
            Show
            Fish
            No data available
            Antibodies
            No data available
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            1 - 1 of 1
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            Mapping
            No data available
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            Citation
            Huang, Y., Yu, S.H., Zhen, W.X., Cheng, T., Wang, D., Lin, J.B., Wu, Y.H., Wang, Y.F., Chen, Y., Shu, L.P., Wang, Y., Sun, X.J., Zhou, Y., Yang, F., Hsu, C.H., Xu, P.F. (2021) Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2. Theranostics. 11:6891-6904.