3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells

• Published in: International journal of cancer Vol. 130; no. 11; pp. 2557 - 2567
• Main Authors: Chiba, Tetsuhiro, Suzuki, Eiichiro, Negishi, Masamitsu, Saraya, Atsunori, Miyagi, Satoru, Konuma, Takaaki, Tanaka, Satomi, Tada, Motohisa, Kanai, Fumihiko, Imazeki, Fumio, Iwama, Atsushi, Yokosuka, Osamu
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosylhomocysteinase - antagonists & inhibitors; Animals; Biological and medical sciences; Cancer; cancer stem cell; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell Line, Tumor; DNA Methylation; DNA-Binding Proteins - physiology; DZNep; Enhancer of Zeste Homolog 2 Protein; EZH2; Gastroenterology. Liver. Pancreas. Abdomen; hepatocellular carcinoma; Histones - metabolism; Humans; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical research; Medical sciences; Mice; Neoplastic Stem Cells - drug effects; Polycomb Repressive Complex 2; Stem cells; Transcription Factors - physiology; tumor-initiating cell; Tumors; Histone-lysine N-methyltransferase; Enzyme; Transferases; Stem cell; Hepatic disease; Hepatocellular carcinoma; Transcription repressor; tumor-initiating cell; Malignant tumor; DZNep; Eradication; Liver cancer; Cancerology; Treatment; Methyltransferases; Liver tumor; cancer stem cell; Ezh2 gene; Digestive diseases; Tumor cell; Cancer; EZH2
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26264

Recent advances in stem cell biology have identified tumor‐initiating cells (TICs) in a variety of cancers including hepatocellular carcinoma (HCC). Polycomb group gene products such as BMI1 and EZH2 have been characterized as general self‐renewal regulators in a wide range of normal stem cells and TICs. We previously reported that Ezh2 tightly regulates the self‐renewal and differentiation of murine hepatic stem/progenitor cells. However, the role of EZH2 in tumor‐initiating HCC cells remains unclear. In this study, we conducted loss‐of‐function assay of EZH2 using short‐hairpin RNA and pharmacological inhibition of EZH2 by an S‐adenosylhomocysteine hydrolase inhibitor, 3‐deazaneplanocin A (DZNep). Both EZH2‐knockdown and DZNep treatment impaired cell growth and anchorage‐independent sphere formation of HCC cells in culture. Flow cytometric analyses revealed that the two approaches decreased the number of epithelial cell adhesion molecule (EpCAM)+ tumor‐initiating cells. Administration of 5‐fluorouracil (5‐FU) or DZNep suppressed the tumors by implanted HCC cells in non‐obese diabetic/severe combined immunodeficient mice. Of note, however, DZNep but not 5‐FU predominantly reduced the number of EpCAM+ cells and diminished the self‐renewal capability of these cells as judged by sphere formation assays. Our findings reveal that tumor‐initiating HCC cells are highly dependent on EZH2 for their tumorigenic activity. Although further analyses of TICs from primary HCC would be necessary, pharmacological interference with EZH2 might be a promising therapeutic approach to targeting tumor‐initiating HCC cells.