RRC ID 44802
Author Nakagawa S, Sakamoto Y, Okabe H, Hayashi H, Hashimoto D, Yokoyama N, Tokunaga R, Sakamoto K, Kuroki H, Mima K, Beppu T, Baba H.
Title Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells.
Journal Oncol Rep
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.
Volume 31(2)
Pages 983-8
Published 2014-2-1
DOI 10.3892/or.2013.2922
PMID 24337160
MeSH Adenosine / analogs & derivatives* Adenosine / pharmacology Antimetabolites, Antineoplastic / pharmacology Antineoplastic Combined Chemotherapy Protocols / pharmacology Apoptosis / drug effects Bile Duct Neoplasms / drug therapy Bile Duct Neoplasms / genetics Bile Ducts, Intrahepatic / pathology Cell Line, Tumor Cell Proliferation / drug effects Cholangiocarcinoma / drug therapy* Cholangiocarcinoma / genetics Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis DNA Methylation / drug effects Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Enhancer of Zeste Homolog 2 Protein Enzyme Inhibitors / pharmacology Epigenesis, Genetic / drug effects* G1 Phase Cell Cycle Checkpoints / drug effects Gemcitabine Humans Polycomb Repressive Complex 2 / antagonists & inhibitors* Polycomb Repressive Complex 2 / biosynthesis Polycomb Repressive Complex 2 / genetics RNA Interference RNA, Small Interfering
IF 3.417
Times Cited 29
Human and Animal Cells RBE(RCB1292) TFK-1(RCB2537)