Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer
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Shinya Oki1, Kenbun Sone1, Katsutoshi Oda1, Ryuji Hamamoto2, Masako Ikemura3, Daichi Maeda4, Makoto Takeuchi1, Michihiro Tanikawa1, Mayuyo Mori-Uchino1, Kazunori Nagasaka1, Aki Miyasaka1, Tomoko Kashiyama1, Yuji Ikeda1, Takahide Arimoto1, Hiroyuki Kuramoto5, Osamu Wada-Hiraike1, Kei Kawana1, Masashi Fukayama3, Yutaka Osuga1 and Tomoyuki Fujii1
1Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
2Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
3Department of Pathology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
4Department of Pathology, Faculty of Medicine, Akita University, Akita 010-8543, Japan
5Center for Female Preventive Medicine, Kanagawa Health Service Association, Naka-ku, Yokohama, Kanagawa 231-0021, Japan
Kenbun Sone, email: [email protected]
Keywords: histone methyltransferase, EZH2, endometrial cancer, GSK126, H3K27 trimethylation
Received: August 15, 2016 Accepted: February 17, 2017 Published: March 17, 2017
The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues. Kaplan-Meier survival analysis using data of the TCGA RNA-seq database and tissue microarrays (TMAs) indicated that EZH2 overexpression is associated with endometrial cancer prognosis. In addition, knockdown of EZH2 using specific siRNAs resulted in growth suppression and apoptosis induction of endometrial cancer cells, accompanied by attenuation of H3K27 trimethylation. Consistent with these results, treatment with GSK126, a specific EZH2 inhibitor, suppressed endometrial cancer cell growth and decreased the number of cancer cell colonies. Furthermore, GSK126 showed additive effects with doxorubicin or cisplatin, which are conventional drugs for treatment of endometrial cancer. Further studies should explore the therapeutic potential of inhibiting EZH2 in patients with endometrial cancer.
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