A Project Developing a New Cancer Therapy Targeting Histone Methyltransferase and Demethylase in ovarian cancer and endometrial cancer

• Project/Area Number: 15K20128
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: Sone Kenbun 東京大学, 医学部附属病院, 助教 (90598872)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: エピジェネティクス / 子宮体癌 / 卵巣癌 / メチル化 / 脱メチル化 / ヒストンメチル化酵素 / ＥＺＨ２ / ヒストン脱メチル化酵素 / EZH2 / SUV420H1

Outline of Final Research Achievements

We investigated the involvement of histone methyltransferase and demethylase in ovarian cancer and endometrial cancer and evaluated its therapeutic potential. At first, we investigated the expression and function of histone methyltransferase 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 normal control cells and tissues. In addition, knockdown of EZH2 using specific siRNAs resulted in growth suppression and apoptosis induction of endometrial cancer cells. Consistent with these results, treatment with a specific EZH2 inhibitor, suppressed endometrial cancer cell growth. Further studies should explore the therapeutic potential of inhibiting EZH2 in patients with endometrial cancer.

Research Products

• [Journal Article] Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer. (2017)
  • Author(s): Oki S, Sone K, Oda K, Hamamoto R, Ikemura M, Maeda D, Takeuchi M, Tanikawa M, Mori-Uchino M, Nagasaka K, Miyasaka A, Kashiyama T, Ikeda Y, Arimoto T, Kuramoto H, Wada-Hiraike O, Kawana K, Fukayama M, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: in press Issue: 25 Pages: 40402-40411
  • DOI: 10.18632/oncotarget.16316
  • NAID: 120007089062
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells (2015)
  • Author(s): Theodore Vougiouklakis,,Kenbun Sone, Vassiliki Saloura, Hyun-Soo Cho, Takehiro Suzuki, Naoshi Dohmae, Houda Alachkar, Yusuke Nakamura, Ryuji Hamamoto
  • Journal Title: Oncotarget Volume: 41 Issue: 41 Pages: 43162-71
  • DOI: 10.18632/oncotarget.6351
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prognostic importance of CDK4/6-specific activity as a predictive marker for recurrence in patients with endometrial cancer, with or without adjuvant chemotherapy. (2015)
  • Author(s): keda Y, Oda K, Ishihara H, Wada-Hiraike O, Miyasaka A, Kashiyama T, Inaba K, Fukuda T, Sone K, Matsumoto Y, Arimoto T, Maeda D, Ikemura M, Fukayama M, Kawana K, Yano T, Aoki D, Osuga Y, Fujii T.
  • Journal Title: Br J Cancer Volume: 113 Issue: 10 Pages: 1477-1483
  • DOI: 10.1038/bjc.2015.369
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas. (2015)
  • Author(s): Inaba K, Oda K, Ikeda Y, Sone K, Miyasaka A, Kashiyama T, Fukuda T, Uehara Y, Arimoto T, Kuramoto H, Wada-Hiraike O, Kawana K, Yano T, Osuga Y, Fujii T.
  • Journal Title: Gynecol Oncol Volume: 138 Issue: 2 Pages: 323-331
  • DOI: 10.1016/j.ygyno.2015.05.031
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PI3K/mTOR pathway inhibition overcomes radioresistance via suppression of the HIF1-α/VEGF pathway in endometrial cancer. (2015)
  • Author(s): Miyasaka A, Oda K, Ikeda Y, Sone K, Fukuda T, Inaba K, Makii C, Enomoto A, Hosoya N, Tanikawa M, Uehara Y, Arimoto T, Kuramoto H, Wada-Hiraike O, Miyagawa K, Yano T, Kawana K, Osuga Y, Fujii T.
  • Journal Title: Gynecol Oncol Volume: 138 Issue: 1 Pages: 174-180
  • DOI: 10.1016/j.ygyno.2015.04.015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The anti-malarial chloroquine suppresses proliferation and overcomes cisplatin resistance of endometrial cancer cells via autophagy inhibition. (2015)
  • Author(s): Fukuda T, Oda K, Wada-Hiraike O, Sone K, Inaba K, Ikeda Y, Miyasaka A, Kashiyama T, Tanikawa M, Arimoto T, Kuramoto H, Yano T, Kawana K, Osuga Y, Fujii T.
  • Journal Title: Gynecol Oncol Volume: 137 Issue: 3 Pages: 538-545
  • DOI: 10.1016/j.ygyno.2015.03.053
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Histone methyl/demthyltrasnferases are novel targets of anti-cancer therapy in endometrial cancer. (2016)
  • Author(s): Shinya Oki, Kenbun Sone, Katsutoshi Oda, Chinami Makii, Kayo Asada, Agapiti Chuwa, Makoto Takeuchi, Osamu Hiraike-Wada, Hiroyuki Kuramoto, Kei Kawana, Yutaka Osuga, Tomoyuki Fujii
  • Organizer: 日本産婦人科学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-22
• [Presentation] The histone methyltransferase, SUV39H2, is a potent target of anticancer therapy in endometrial cancer (2016)
  • Author(s): Kenbun Sone, Katsutoshi Oda, Shinya Oki, Makoto Takeuchi, Agapiti Hipoliti Chuwa ,Chinami Makii, Tomoko Kashiyama, Yuji Ikeda, Osamu Wada-Hiraike, Kei Kawana, Yutaka Osuga, Tomoyuki Fujii
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2016-04-21
• [Presentation] The histone methyltransferase EZH2 is a novel target of anti-cancer therapy in endometrial cancer (2016)
  • Author(s): Shinya Oki, Kenbun Sone, Katsutoshi Oda, Akira Nishijima, Makoto Takeuchi, Agapiti Chuwa, Kayo Asada, Chinami Makii,Kei Kawana, Yutaka Osuga, Tomoyuki Fujii,
  • Organizer: AACR annual meeting
  • Place of Presentation: ニューオーリンズ
  • Year and Date: 2016-04-18
  • Int'l Joint Research
• [Presentation] The histone methyltransferase EZH2 is a novel target of anti-cancer therapy in endometrial cancer. (2016)
  • Author(s): Shinya Oki, Kenbun Sone, Katsutoshi Oda, Akira Nishijima, Makoto Takeuchi, Agapiti Chuwa, Kayo Asada, Chinami Makii, Kei Kawana, Yutaka Osuga, Tomoyuki Fujii
  • Organizer: 2016 AACR annual meeting
  • Place of Presentation: Ernest N. Morial Convention Center New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research