Analysis of molecular mechanisms of cell proliferation in BAP1-mutated cancer using synthetic lethal phenotypes

• Project/Area Number: 18K06979
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Tokyo University of Technology (2019-2020); Juntendo University (2018)
• Principal Investigator: Murakami-Tonami Yuko 東京工科大学, 応用生物学部, 教授 (70405174)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 合成致死 / 悪性中皮腫 / DNA損傷修復 / BAP1

Outline of Final Research Achievements

We analyzed USP1 and CHK2 among the genes that showed synthetic lethal phenotype for BAP1 mutation in cultured cells.The following results were obtained. (1) FANCD2, which has been reported as a target protein of the deubiquitinating enzyme USP1, is also deubiquitinated in BAP1 in vitro, (2) knockdown of BAP1 in malignant mesothelioma cell lines delays the S phase, and (3) inhibiting USP1/CHK2 blocks cancer growth in tumor-bearing mice using BAP1 mutant cells.

Academic Significance and Societal Importance of the Research Achievements

BAP1遺伝子はがん抑制遺伝子であるため、その変異によって起こるがんに対する抗がん剤開発では直接標的にしにくいという問題がある。そこで合成致死表現型を用い、将来的に標的になる可能性がある分子標的の探索をするとともに、候補遺伝子の新しい機能を解析した。

Research Products

• [Journal Article] Synthesis and Biological Evaluation of NMDI-14 Derivatives as anti-Mesothelioma Agents (2020)
  • Author(s): Hong Nhung Nguyen, Koya Suzuki, Yasuaki Kimura, Takatsugu Hirokawa, Yuko Murakami-Tonami, and Hiroshi Abe
  • Journal Title: Heterocycles Volume: 100 Issue: 2 Pages: 253-266
  • DOI: 10.3987/com-19-14191
  • Peer Reviewed / Open Access
• [Journal Article] Synthetic lethality in the search for novel molecular targets in cancer therapeutics (2019)
  • Author(s): Murakami-Tonami Y
  • Journal Title: Juntendo Medical Journal Volume: 65 Pages: 292-296
  • Peer Reviewed / Open Access
• [Journal Article] A Covalent Inhibitor for Glutathione S‐Transferase Pi (GSTP1‐1) in Human Cells (2019)
  • Author(s): Shishido Yuko、Tomoike Fumiaki、Kuwata Keiko、Fujikawa Haruka、Sekido Yoshitaka、Murakami‐Tonami Yuko、Kameda Tomoshi、Abe Naoko、Kimura Yasuaki、Shuto Satoshi、Abe Hiroshi
  • Journal Title: ChemBioChem Volume: 20 Issue: 7 Pages: 900-905
  • DOI: 10.1002/cbic.201800671
  • Peer Reviewed
• [Presentation] LATS2変異を有した悪性中皮腫に対する合成致死誘導機構の検討 (2020)
  • Author(s): 鈴木 浩也、山岸 良多、向井 智美、田部 陽子、三井田 孝、村上 浩士、関戸 好孝、村上(渡並) 優子
  • Organizer: 日本薬学会第140年会
• [Presentation] 悪性中皮腫原因遺伝子変異に対する新規合成致死標的の探索 (2020)
  • Author(s): 村上（渡並） 優子、佐藤 綾人、鈴木 浩也、三井田 孝、村上 浩士、関戸 好孝
  • Organizer: 日本薬学会第140年会
• [Presentation] リン酸フルオリド型プロドラッグの開発 (2020)
  • Author(s): 吉田 祐希、Zheng Ti、伏原 大地、新美 結士、中本 航介、橋谷 文貴、木村 康明、日吉 貴子、齋木 由利子、堀井 明、鈴木 哲朗、村上 優子、阿部 洋
  • Organizer: 日本薬学会第140年会
• [Presentation] Search for new synthetic lethal target for malignant mesothelioma using small molecule compound library (2020)
  • Author(s): Yuko Murakami-Tonami, Koya Suzuki, Takashi Miida, Hiroshi Abe, Yoshitaka Sekido
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Molecular mechanism of synthetic lethality induced by SMG6 inhibition in LATS2-mutated mesothelioma cells (2020)
  • Author(s): Koya Suzuki, Ryota Yamagishi, Satomi Mukai, Yoko Tabe, Takashi Miida, Hiroshi Murakami, Yoshitaka Sekido, Yuko Murakami-Tonami
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Phosphorylation of Mei4 by Cds1 in the meiotic DNA replication checkpoint linking pre-meiotic DNA replication and meiotic recombination in fission yeast (2019)
  • Author(s): Hiroshi Murakami, Seiji Kosuge, Takatomi Yamada, Hirofumi Aiba, Yuko Murakami
  • Organizer: EMBO Workshop on 10th International Fission Yeast Meeting
  • Int'l Joint Research
• [Presentation] CAGE transcriptome analysis reveals BCL2A1 upregulation in FLT3-ITD/D835 dual mutated AML cells harboring complex co-mutations (2019)
  • Author(s): Kotoko Yamatani, Tomohiko Ai, Kaori Saitoh, Haeun Yang, Koya Suzuki,Atsushi Hori, Yuko Murakami-Tonami, Weiguo Zhang, Bing Carter, Sonoko Kinjo, Kazuho Ikeo, Kazuhiro Katayama, Yoshikazu Sugimoto, Hironori Harada, Takashi Miida, Neil P. Shah, Marina Konopleva, Yoshihide Hayashizaki, Michael Andreeff, Yoko Tabe
  • Organizer: 61st ASH (American Society of Hematology) Meeting
  • Int'l Joint Research
• [Presentation] OxPhos inhibition induces formation of tunneling nanotubes in AML cells and facilitates mitochondrial transfer from BM stroma to AML that contributes to microenvironment-mediated drug-resistance of AML (2019)
  • Author(s): Haeun Yang, Yoko Tabe, Kaori Saitoh, Kotoko Yamatani, Rodrigo Jacamo, Helen Ma, Vivian Ruvolo, Qi Zhang, Vinitha Kuruvilla, Natalia Baran, Junichi Imoto, Kazuho Ikeo, Kaori Moriya, Yuko Murakami-Tonami, Koya Suzuki, Takashi Miida, Michael Andreeff, Christopher Vellano, Joseph R. Marszalek, Marina Konopleva
  • Organizer: 61st ASH (American Society of Hematology) Meeting
  • Int'l Joint Research
• [Presentation] LATS2変異を有した悪性腫瘍における合成致死を基盤とした細胞死誘導機構の検討 (2019)
  • Author(s): 鈴木浩也、向井智美、田部陽子、三井田孝、関戸好孝、村上（渡並）優子
  • Organizer: 第23回日本がん分子標的治療学会学術総会
• [Presentation] LATS2変異を有した悪性腫瘍における合成致死を基盤とした細胞死誘導機構の検討 (2019)
  • Author(s): 鈴木 浩也、山岸 良多、向井 智美、田部 陽子、三井田 孝、村上 浩士、関戸 好孝、村上（渡並） 優子
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 分裂酵母における DNA 複製と相同組換え開始を制御する Cds1 キナーゼと転写因子 Mei4 の機能解析 (2019)
  • Author(s): 小菅清二、山田貴富、村上優子、饗場浩文、村上浩士
  • Organizer: 酵母遺伝学フォーラム第52回研究報告会
• [Presentation] 急性骨髄性白血病における酸化的リン酸化阻害による代謝抑制効果とミトコンドリア移動 (2019)
  • Author(s): 齋藤 香里, 梁 夏恩, 鈴木 浩也, 村上 優子, 三井田 孝, 田部 陽子
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 合成致死表現型を指標とした新規悪性中皮腫治療薬標的の探索 (2018)
  • Author(s): 村上（渡並）優子
  • Organizer: 先進ゲノム支援 拡大班会議
• [Presentation] 藤川遥加, 宍戸裕子, 木村康明, 友池史明, 村上優子, 青木正博, 阿部洋 (2018)
  • Author(s): 共有結合型GST阻害剤の開発
  • Organizer: 日本化学会 第98春季年会
• [Presentation] Identification of the genes which show synthetic lethal phenotype with BAP1 mutations in malignant mesothelioma cells (2018)
  • Author(s): Yuko Murakami-Tonami, Shinichi Kiyonari, Yoko Tabe, Kenji Kadomatsu, Takashi Miida, Yoshitaka Sekido
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 急性骨髄性白血病における酸化的リン酸化阻害の抗腫瘍効果 (2018)
  • Author(s): 齋藤 香里、梁 夏恩、村上(渡並) 優子、鈴木 浩也、三井田 孝、田部 陽子
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 分裂酵母 DNA複製チェックポイントキナーゼ Cds1による転写因子 Mei4のリン酸化を介した減数分裂相同組換えの制御機構 (2018)
  • Author(s): 小菅 清二、山田 貴富、饗場 浩文、村上 優子、村上 浩士
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 悪性中皮腫におけるBAP1遺伝子変異に対する合成致死遺伝子の網羅的探索 (2018)
  • Author(s): 村上（渡並）優子、天野美希、小木曽杏奈、清成信一、紅朋浩、田部陽子、金田典雄、門松健治、三井田孝、村上浩士、関戸好孝
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. (2018)
  • Author(s): Kotoko Yamatani, Yoko Tabe, Kaori Saitoh, Haeun Yang, Yuko Tonami-Murakami, Koya Suzuki, Weiguo Zhang, Sonoko Kinjo, Kazuho Ikeo, Kaoru Mogushi, Masaki Hosoya, Shigeo Yamaguchi, Hironori Harada9, Takashi Miida, Neil P. Shah, Yoshihide Hayashizaki, Marina Konopleva, Michael Andreeff
  • Organizer: 61st American Society of Hematology Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Combined targeting of Bcl-2 and XPO1 overcomes acquired resistance to tyrosine kinase inhibitors in FLT3-ITD/TKD double mutant AML. (2018)
  • Author(s): Yoko Tabe, Kotoko Yamatani, Haeun Yang, Kaori Saito, Yuko Tonami-Murakami, Koya Suzuki, Weiguo Zhang, Sonoko Kinjo, Kazuho Ikeo, Masaki Hosoya, Kaoru Mogushi, Shigeo Yamaguchi, Hironori Harada, Takashi Miida, Neil P. Shah, Yoshihide Hayashizaki, Marina Konopleva, Michael Andreeff
  • Organizer: 61st American Society of Hematology Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] 悪性中皮腫におけるBAP1遺伝子変異に対する合成致死遺伝子の網羅的探索 (2018)
  • Author(s): 村上（渡並）優子
  • Organizer: 先進ゲノム支援拡大班会議
• [Patent(Industrial Property Rights)] LATS2変異疾患のための分子標的及びその利用 (2019)
  • Inventor(s): 村上優子・鈴木浩也・三井田孝・関戸好孝・向井智美・山岸良多
  • Industrial Property Rights Holder: 村上優子・鈴木浩也・三井田孝・関戸好孝・向井智美・山岸良多
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 悪性中皮腫の治療剤 (2019)
  • Inventor(s): 村上優子・佐藤綾人・三井田孝・関戸好孝
  • Industrial Property Rights Holder: 村上優子・佐藤綾人・三井田孝・関戸好孝
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019