Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

Nakagawa,Shigeki; Sakamoto,Yasuo; Okabe,Hirohisa; Hayashi,Hiromitsu; Hashimoto,Daisuke; Yokoyama,Naomi; Tokunaga,Ryuma; Sakamoto,Keita; Kuroki,Hideyuki; Mima,Kosuke; Beppu,Toru; Baba,Hideo

doi:10.3892/or.2013.2922

Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells

Authors:
- Shigeki Nakagawa
- Yasuo Sakamoto
- Hirohisa Okabe
- Hiromitsu Hayashi
- Daisuke Hashimoto
- Naomi Yokoyama
- Ryuma Tokunaga
- Keita Sakamoto
- Hideyuki Kuroki
- Kosuke Mima
- Toru Beppu
- Hideo Baba
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Affiliations: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
Published online on: December 13, 2013 https://doi.org/10.3892/or.2013.2922
Pages: 983-988

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Abstract

Enhancer of zeste homolog 2 (EZH2) is involved in malignant transformation and the biological aggressiveness of several human malignancies. Growing evidence indicates that EZH2 may be an appropriate therapeutic target for malignancies, including cholangiocarcinoma. Recently, an S-adenosyl-L-homocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep) was shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep and the combination of gemcitabine and DZNep in cholangiocarcinoma cells. The effects of DZNep and its combination with gemcitabine were assessed in the cholangiocarcinoma cell lines RBE and TFK-1. DZNep depleted the cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. DZNep treatment resulted in the inhibition of proliferation in the cholangiocarcinoma cell lines, and the combination of DZNep and gemcitabine showed synergistic inhibition of cell proliferation. DZNep induced apoptosis and G1 phase cell cycle arrest in cholangiocarcinoma cells, and the combination of DZNep and gemcitabine enhanced the induced apoptosis and G1 arrest when compared with gemcitabine alone. Inhibition of cell proliferation by DZNep was partially associated with upregulation of p16INK4a and p17KIP1. The present study shows that DZNep inhibits cell proliferation by inducing G1 arrest and apoptosis. These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach for the treatment of cholangiocarcinoma.

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