Epigenetic network between histon modification and miRNA in ovarian clear cell carcinoma

• Project/Area Number: 19K09775
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Tsuruga Tetsushi 東京大学, 医学部附属病院, 講師 (70570448)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ヒストン修飾 / エピゲノムj / 卵巣類内膜癌 / 子宮体癌 / ヒストンメチル化酵素 / EHMT2 / CARM1 / エピゲノムネットワーク / 卵巣癌 / エピゲノム / DNAメチル化 / miRNA / 卵巣明細胞癌 / WHSC1 / SMYD2 / ChIP-seq

Outline of Research at the Start

エピゲノムの異常は癌化メカニズムの一翼を担っており、その解明は癌治療において重要な役割を担っている。エピゲノム因子の中でDNAメチル化は広く研究され ているが、婦人科癌においてヒストン修飾、miRNAは研究が遅れている。今回、治療抵抗性で、本邦で頻度が高い卵巣明細胞癌のヒストン修飾とmiRNAのエピゲノム ネットワークについて解明する。ヒストン修飾酵素、miRNAはそれぞれ多層的な遺伝子調整をしており、両者のネットワークは非常に複雑であるため人工知能による深層学習を利用してマルチオミックス解析を行う。最終的に新規治療標的予測因子―エピゲノムバイオマーカー、新しいエピゲノム治療薬の開発を目指す。

Outline of Final Research Achievements

① Therapeutic target of histone methylase EHMT2 in ovarian endometrioid carcinoma was investigated. Increased expression of EMHT2 was observed in ovarian endometrioid carcinoma, and addition of siRNA for EHMT2 and EHMT2 inhibitors to ovarian endometrioid carcinoma suppressed cell proliferation with increasing inflammatory markers and inducing apoptosis. (2) Examination of histone methyl-transferases PRMT6 in endometrial cancer: The mRNA expression level of PRMT6 was high in endometrial cancer, showing a negative correlation with prognosis (p < 0.01). ChIP-seq analysis showed PRMT6 regulate multiple cancer-related transcription factors and interferon factors through histone modification. And, there was the relation of histone H3R2 methylation and histone H3K 27 acetylation.

Academic Significance and Societal Importance of the Research Achievements

今までフォーカスされていなかった卵巣類内膜癌に治療標的の可能性、そのメカニズムについて同定した。また子宮体癌に対するPRMT6の治療標的の可能性も追求し、エピゲノムを用いた網羅的解析により様々な新規遺伝子を同定する事ができた。また子宮体癌におけるヒストン修飾間のエピゲノムネットワークも明らかにされ、今後の子宮体癌の治療標的同定に貢献する研究と考える。

Research Products

• [Journal Article] Histone arginine methyltransferase CARM1 selective inhibitor TP-064 induces apoptosis in endometrial cancer (2022)
  • Author(s): Inoue Futaba、Sone Kenbun、Toyohara Yusuke、Tanimoto Saki、Takahashi Yu、Kusakabe Misako、Kukita Asako、Honjoh Harunori、Nishijima Akira、Taguchi Ayumi、Miyamoto Yuichiro、Tanikawa Michihiro、Iriyama Takayuki、Uchino Mayuyo-mori、Tsuruga Tetsushi、Wada-Hiraike Osamu、Oda Katsutoshi、Osuga Yutaka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 601 Pages: 123-128
  • DOI: 10.1016/j.bbrc.2022.02.086
  • Peer Reviewed / Open Access
• [Journal Article] The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma (2022)
  • Author(s): Hidenori Machino, Syuzo Kaneko, Masaaki Komatsu, Noriko Ikawa, Ken Asada, Ryuichiro Nakato, Kanto Shozu, Ai Dozen, Kenbun Sone, Hiroshi Yoshida, Tomoyasu Kato, Katsutoshi Oda, Yutaka Osuga, Tomoyuki Fujii, Gottfried von Keudell, Vassiliki Saloura, Ryuji Hamamoto
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 39-39
  • DOI: 10.1038/s42003-021-02992-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic diagnosis of pseudomyxoma peritonei originating from mucinous borderline tumor inside an ovarian teratoma (2022)
  • Author(s): Taguchi Ayumi、Rokutan Hirofumi、Oda Katsutoshi、Tanikawa Michihiro、Tanimoto Saki、Sone Kenbun、Mori Mayuyo、Tsuruga Tetsushi、Kohsaka Shinji、Tatsuno Kenji、Shinozaki-Ushiku Aya、Miyagawa Kiyoshi、Mano Hiroyuki、Aburatani Hiroyuki、Ushiku Tetsuo、Osuga Yutaka
  • Journal Title: BMC Medical Genomics Volume: 15 Issue: 1 Pages: 51-51
  • DOI: 10.1186/s12920-022-01188-x
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent cervical cancer with PD-L1 amplification treated with nivolumab: A case enrolled in the BELIEVE trial (2022)
  • Author(s): Yoshimoto Daisuke、Taguchi Ayumi、Tanikawa Michihiro、Sone Kenbun、Shimoi Tatsunori、Tsuruga Tetsushi、Oda Katsutoshi、Osuga Yutaka
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: NA Issue: 7 Pages: 2010-2014
  • DOI: 10.1111/jog.15240
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer (2020)
  • Author(s): Wada Miku、Kukita Asako、Sone Kenbun、Hamamoto Ryuji、Kaneko Syuzo、Komatsu Masaaki、Takahashi Yu、Inoue Futaba、Kojima Machiko、Honjoh Harunori、Taguchi Ayumi、Kashiyama Tomoko、Miyamoto Yuichiro、Tanikawa Michihiro、Tsuruga Tetsushi、Mori-Uchino Mayuyo、Wada-Hiraike Osamu、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Biomolecules Volume: 10 Issue: 12 Pages: 1686-1686
  • DOI: 10.3390/biom10121686
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells (2020)
  • Author(s): Kojima Machiko、Sone Kenbun、Oda Katsutoshi、Hamamoto Ryuji、Kaneko Syuzo、Oki Shinya、Kukita Asako、Kawata Akira、Honjoh Harunori、Kawata Yoshiko、Kashiyama Tomoko、Sato Masakazu、Taguchi Ayumi、Miyamoto Yuichiro、Tanikawa Michihiro、Tsuruga Tetsushi、Nagasaka Kazunori、Wada?Hiraike Osamu、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Oncology Letters Volume: 20 Issue: 5 Pages: 1-1
  • DOI: 10.3892/ol.2020.12014
  • Peer Reviewed / Open Access
• [Journal Article] The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation (2019)
  • Author(s): Kojima Machiko、Sone Kenbun、Wada-Hiraike Osamu、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 455-455
  • DOI: 10.1186/s12885-019-5638-9
  • Peer Reviewed / Open Access
• [Journal Article] The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation. (2019)
  • Author(s): Tsuruga T, Hirata T, Akiyama I, Matsumoto Y, Oda K, Fujii T, Osuga Y.
  • Journal Title: J Obstet Gynaecol Res. Volume: 45（8） Issue: 8 Pages: 1613-1618
  • DOI: 10.1111/jog.14014
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma. (2019)
  • Author(s): Makii C, Ikeda Y, Oda K, Uehara Y, Nishijima A, Koso T, Kawata Y, Kashiyama T, Miyasaka A, Sone K, Tanikawa M, Tsuruga T, Mori-Uchino M, Nagasaka K, Matsumoto Y, Wada-Hiraike O, Kawana K, Hasegawa K, Fujiwara K, Aburatani H, Osuga Y, Fujii T.
  • Journal Title: Gynecol Oncol. Volume: 155（2） Pages: 331-339
  • Peer Reviewed
• [Journal Article] Interleukin-17 is associated with expression of programmed cell death 1 ligand 1 in ovarian carcinoma. (2019)
  • Author(s): Aotsuka A, Matsumoto Y, Arimoto T, Kawata A, Ogishima J, Taguchi A, Tanikawa M, Sone K, Mori-Uchino M, Tsuruga T, Oda K, Kawana K, Osuga Y, Fujii T.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 10 Pages: 3068-3078
  • DOI: 10.1111/cas.14174
  • Peer Reviewed / Open Access