Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer

// Shinya Oki 1 , Kenbun Sone 1 , Katsutoshi Oda 1 , Ryuji Hamamoto 2 , Masako Ikemura 3 , Daichi Maeda 4 , Makoto Takeuchi 1 , Michihiro Tanikawa 1 , Mayuyo Mori-Uchino 1 , Kazunori Nagasaka 1 , Aki Miyasaka 1 , Tomoko Kashiyama 1 , Yuji Ikeda 1 , Takahide Arimoto 1 , Hiroyuki Kuramoto 5 , Osamu Wada-Hiraike 1 , Kei Kawana 1 , Masashi Fukayama 3 , Yutaka Osuga 1 and Tomoyuki Fujii 1 1 Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan 2 Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan 3 Department of Pathology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan 4 Department of Pathology, Faculty of Medicine, Akita University, Akita 010-8543, Japan 5 Center for Female Preventive Medicine, Kanagawa Health Service Association, Naka-ku, Yokohama, Kanagawa 231-0021, Japan Correspondence to: Kenbun Sone, email: sonekenbun@hotmail.co.jp Keywords: histone methyltransferase, EZH2, endometrial cancer, GSK126, H3K27 trimethylation Received: August 15, 2016      Accepted: February 17, 2017      Published: March 17, 2017 ABSTRACT 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.