title: Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells.
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.
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Shigeki
authors: S
authors: Nakagawa
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Yasuo
authors: Y
authors: Sakamoto
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Hirohisa
authors: H
authors: Okabe
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Hiromitsu
authors: H
authors: Hayashi
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Daisuke
authors: D
authors: Hashimoto
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Naomi
authors: N
authors: Yokoyama
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Ryuma
authors: R
authors: Tokunaga
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Keita
authors: K
authors: Sakamoto
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Hideyuki
authors: H
authors: Kuroki
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Kosuke
authors: K
authors: Mima
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Toru
authors: T
authors: Beppu
authors: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
authors: Hideo
authors: H
authors: Baba
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000235:genetics; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D019175:DNA Methylation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D050760:Cyclin-Dependent Kinase Inhibitor p27; C048460:3-deazaneplanocin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000241:Adenosine; D000093542:Gemcitabine