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3‐Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor‐initiating hepatocellular carcinoma cells
Author(s) -
Chiba Tetsuhiro,
Suzuki Eiichiro,
Negishi Masamitsu,
Saraya Atsunori,
Miyagi Satoru,
Konuma Takaaki,
Tanaka Satomi,
Tada Motohisa,
Kanai Fumihiko,
Imazeki Fumio,
Iwama Atsushi,
Yokosuka Osamu
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26264
Subject(s) - cancer research , ezh2 , stem cell , biology , cancer stem cell , epithelial cell adhesion molecule , progenitor cell , gene knockdown , cell culture , hepatocellular carcinoma , immunology , cell adhesion molecule , microbiology and biotechnology , gene expression , biochemistry , genetics , gene
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.