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A potential antitumor ellagitannin, davidiin, inhibited hepatocellular tumor growth by targeting EZH2

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Tumor Biology

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is the third most common cause of cancer-related deaths. Currently available treatment options for HCC patients are scarce resulting in an urgent need to develop a novel effective cure. Polygonum capitatum is a medicinal herb which has been used to treat inflammatory diseases in Miao nationality of China. We recently isolated a pure compound davidiin from P. capitatum extract. Four HCC cell lines were treated with davidiin. Cell viability was recorded by MTT assay. siRNAs targeting enhancer of zeste homolog 2 (EZH2) were applied to modulate the expression of EZH2. Established xenograft mice models of HCC were applied to evaluate the in vivo anticancer activity of davidiin. We investigated the anticancer activity and the underlying mechanism of davidiin. The compound inhibited HCC cell growth and also suppressed tumor growth in xenografted HCC mouse. Such inhibition was facilitated by specifically downregulation on EZH2. The compound possesses anticancer activity both in vitro and in vivo which warrants further clinical investigation as a potential anti-HCC agent.

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Abbreviations

Bmi-1:

B lymphoma Mo-MLV insertion region 1 homolog

CBX:

Chromobox protein homologue

DMSO:

Dimethylsulfoxide

EDTA:

Ethylenediaminetetraacetic acid

EED:

Embryonic ectoderm development

EZH2:

Enhancer of zeste homolog 2

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HCC:

Hepatocellular carcinoma

HRP:

Horseradish peroxidase

H3K27me3:

Histone H3 trimethylated on lysine 27

MG132:

N-(benzyloxycarbonyl)leucinylleucinylleucinal Z-Leu-Leu-Leu-al

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PARP:

Poly ADP ribose polymerase

PcG protein:

Polycomb group protein

PCR:

Polymerase chain reaction

PH:

Polyhomeotic

PI:

propidium iodide

PRC:

Polycomb repressor complex

PVDF:

Polyvinylidene difluoride

RBAP48:

Retinoblastoma-binding protein p48

SFN:

Sulforaphane

SUZ12:

Suppressor of zeste 12

TCM:

Traditional Chinese medicine

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Acknowledgments

This work was supported by grants from the Research Grants Council General Research Fund of Hong Kong [CUHK462109 and CUHK462211], National Natural Science Foundation of China [81101888], Shenzhen Basic Research Program [JC201105201092A], Direct Grant from CUHK to YC, NSFC grant [81072611], National Science and Technology Special Projects [2012ZX09301002-006], and the Special Fund of Chinese Central Government for Basic Scientific Research Operations [2012CHX08] to YW.

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China

    Yan Wang, Jingyi Ma, Ru Feng & Jie Fu

  2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong

    Sheung Ching Chow, Chi Han Li, Zhangang Xiao & Yangchao Chen

  3. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, 518057, China

    Yangchao Chen

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  1. Yan Wang
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Correspondence to Yangchao Chen.

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Statistical analysis of western blots shown in Figs. 1e and 2a, c. (a) Reduced caspase 3 level and increase in both PARP and caspase 3 cleavages were detected in both Hep3B and Bel7404 cells treated with davidiin. (b) Reduced the levels of EZH2, H3K27me3, and cyclin D1 were observed when Hep3B and Bel7404 were treated with davidiin. (c) Davidiin-induced EZH2 reduction was reversed by MG132, when davidiin-treated HCC cells were co-treated with a proteasome inhibitor, MG132. Transcript levels between groups were considered as significantly different when p < 0.05 (*p < 0.05, **p < 0.01 vs. control, n = 3) (PDF 351 kb)

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Wang, Y., Ma, J., Chow, S.C. et al. A potential antitumor ellagitannin, davidiin, inhibited hepatocellular tumor growth by targeting EZH2. Tumor Biol. 35, 205–212 (2014). https://doi.org/10.1007/s13277-013-1025-3

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  • DOI: https://doi.org/10.1007/s13277-013-1025-3

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