Acceleration and satisfaction of epigenetic drug discovery using profiling technology

• Project/Area Number: 16K15616
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: KOSEKI Jyun 大阪大学, 医学系研究科, 特任助教(常勤) (20616669)
• Co-Investigator(Kenkyū-buntansha): 今野 雅允 大阪大学, 医学系研究科, 寄附講座講師 (80618207) ; 西田 尚弘 大阪大学, 医学系研究科, 助教 (50588118) ; 川本 弘一 大阪大学, 医学部附属病院, その他 (30432470)
• Co-Investigator(Renkei-kenkyūsha): ISHII Hideshi 大阪大学, 大学院医学系研究科, 特任教授 (10280736)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌 / エピゲノム / 創薬 / インシリコスクリーニング

Outline of Final Research Achievements

It was very difficult in the past to screen inhibitors of JARID1B, one of epigenome regulatory factor. We have made it possible using our in silico screening technologies with large-scale computer. In silico screening has been already performed to pick up the candidate compounds from five million drug like compounds. Then, we selected first lead compounds from the picked up candidate compounds with chemical assay. We have investigated the in vitro anti-cancer effects of these lead compounds, and the after, investigated the in vivo anti-cancer effects for the part of them. We succeeded in establishing a pathway to show the synthetic evolution guidelines for lead compounds based on the functional information from these experimental results. According to this procedure, it is possible to design a more efficient drug structure.

Research Products

• [Journal Article] Enzymes of the one-carbon folate metabolism as anticancer targets predicted by survival rate analysis (2018)
  • Author(s): Koseki Jun、Konno Masamitsu、Asai Ayumu、Colvin Hugh、Kawamoto Koichi、Nishida Naohiro、Sakai Daisuke、Kudo Toshihiro、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Sci Rep. Volume: 8 Pages: 303
  • DOI: 10.1038/s41598-017-18456-x
  • Peer Reviewed / Open Access
• [Journal Article] Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells (2018)
  • Author(s): Konno Masamitsu、Matsui Hidetoshi、Koseki Jun、Asai Ayumu、Kano Yoshihiro、Kawamoto Koichi、Nishida Naohiro、Sakai Daisuke、Kudo Toshihiro、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Sci Rep. Volume: 8 Pages: 899
  • DOI: 10.1038/s41598-018-19284-3
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA profiles involved in trifluridine resistance (2017)
  • Author(s): Tsunekuni Kenta、Konno Masamitsu、Asai Ayumu、Koseki Jun、Kobunai Takashi、Takechi Teiji、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Oncotarget. Volume: 8 Pages: 53017～53027
  • DOI: 10.18632/oncotarget.18078
  • Peer Reviewed / Open Access
• [Journal Article] Low expression of the GOPC is a poor prognostic marker in colorectal cancer (2017)
  • Author(s): Ohara Nobuyoshi、Haraguchi Naotsugu、Koseki Jun、Nishizawa Yujiro、Kawai Kenji、Takahashi Hidekazu、Nishimura Junichi、Hata Taishi、Mizushima Tsunekazu、Yamamoto Hirofumi、Ishii Hideshi、Doki Yuichiro、Mori Masaki
  • Journal Title: Oncol Lett. Volume: 14 Pages: 4483～4490
  • DOI: 10.3892/ol.2017.6817
  • Peer Reviewed / Open Access
• [Journal Article] The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells (2017)
  • Author(s): Taketo Kosuke、Konno Masamitsu、Asai Ayumu、Koseki Jun、Toratani Masayasu、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi、Ogawa Kazuhiko
  • Journal Title: Int J Oncol. Volume: 52 Pages: 621～629
  • DOI: 10.3892/ijo.2017.4219
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia stimulates the cytoplasmic localization of oncogenic long noncoding RNA LINC00152 in colorectal cancer (2017)
  • Author(s): Nishizawa Yujiro、Konno Masamitsu、Asai Ayumu、Koseki Jun、Kawamoto Koichi、Miyoshi Norikatsu、Takahashi Hidekazu、Nishida Naohiro、Haraguchi Naotsugu、Sakai Daisuke、Kudo Toshihiro、Hata Taishi、Matsuda Chu、Mizushima Tsunekazu、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Int J Oncol. Volume: 52 Pages: 453～460
  • DOI: 10.3892/ijo.2017.4218
  • Peer Reviewed / Open Access
• [Journal Article] Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer (2017)
  • Author(s): Nishizawa Yujiro、Konno Masamitsu、Asai Ayumu、Koseki Jun、Kawamoto Koichi、Miyoshi Norikatsu、Takahashi Hidekazu、Nishida Naohiro、Haraguchi Naotsugu、Sakai Daisuke、Kudo Toshihiro、Hata Taishi、Matsuda Chu、Mizushima Tsunekazu、Satoh Taroh、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Oncotarget. Volume: 9 Pages: 7476～7486
  • DOI: 10.18632/oncotarget.23554
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma (2017)
  • Author(s): Ohashi Tomofumi、Eguchi Hidetoshi、Kawamoto Koichi、Konno Masamitsu、Asai Ayumu、Colvin Hugh、Ueda Yuji、Takaoka Hirofumi、Iwagami Yoshifumi、Yamada Daisaku、Asaoka Tadafumi、Noda Takehiro、Wada Hiroshi、Gotoh Kunihito、Kobayashi Shogo、Koseki Jun、Satoh Taroh、Ogawa Kazuhiko、Doki Yuichiro、Mori Masaki、Ishii Hideshi
  • Journal Title: Oncol Rep. Volume: 39 Pages: 1276～1282
  • DOI: 10.3892/or.2017.6172
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer. (2017)
  • Author(s): Nishizawa, Y., Nishida, N., Konno, M., Kawamoto, K., Asai, A., Koseki, J., Takahashi, H., Haraguchi, N., Nishimura, J., Hata, T., Matsuda, C., Mizushima, T., Satoh, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Ann. Surg. Oncol. Volume: 24 Pages: 841-849
  • DOI: 10.1245/s10434-016-5395-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The importance of mitochondrial folate enzymes in human colorectal cancer. (2017)
  • Author(s): Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., Tsunekuni, K., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Oncol. Rep. Volume: 37 Pages: 417-425
  • DOI: 10.3892/or.2016.5264.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High expression of ADAMTS5 is a potent marker for lymphatic invasion and lymph node metastasis in colorectal cancer. (2017)
  • Author(s): Haraguchi, N., Ohara, N., Koseki, J., Takahashi, H., Nishimura, J., Hata, T., Mizushima, T., Yamamoto, H., Ishii, H., Doki, Y., Mori, M.
  • Journal Title: Mol. Clinic. Oncol. Volume: 6 Pages: 130-137
  • DOI: 10.3892/mco.2016.1088.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular Orbital Study of the Formation of Intramolecular Hydrogen Bonding of a Ligand Molecule in a Protein Aromatic Hydrophobic Pocket (2016)
  • Author(s): Koseki, J., Gouda, H., Hirono, S.
  • Journal Title: Chem. Pharm. Bull. Volume: 64 Pages: 1031-1035
  • DOI: 10.1248/cpb.c16-00126.
  • Peer Reviewed
• [Journal Article] MicroRNA miR-374, a potential radiosensitizerfor carbon ion beam radiotherapy. (2016)
  • Author(s): Beak, S-J., Sato, K., Nishida, N., Koseki, J., Azuma, R., Kawamoto, K., konno, M., Hayashi, K., Satoh, T., Doki, Y., Mori, M., Ishii, H., Ogawa, K.
  • Journal Title: Oncol. Rep. Volume: 36 Pages: 2946-2950
  • DOI: 10.3892/or.2016.5122.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial- Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. (2016)
  • Author(s): Colvin, H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J., Hata, T., Kawamoto, K., Asai, A., Tunekuni, K., Koseki, J., Mizushima, T., Satoh, T., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Sci. Rep. Volume: 6 Pages: 36289
  • DOI: 10.1038/srep36289
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] がん幹細胞におけるオルニチン代謝経路のトランスオミックス解析 (2017)
  • Author(s): 小関準、今野雅允、浅井歩、松井秀俊、尾崎みゆ希、佐藤太郎、土岐祐一郎、森正樹、石井秀始
  • Organizer: 第5回がんと代謝研究会 in 札幌
• [Presentation] トランス-オミックス法を用いたがん幹細胞におけるポリアミン代謝経路の意義の解析 (2017)
  • Author(s): 小関準、今野雅允、松井秀俊、加納義弘、佐藤太郎、森正樹、土岐祐一郎、石井秀始
  • Organizer: 第26回日本がん転移学会学術集会・総会
• [Presentation] 新規トランスオミックス法を用いたがん幹細胞における化学療法耐性 の解析 (2017)
  • Author(s): 小関準、今野雅允、浅井歩、佐藤太郎、土岐祐一郎、森正樹、石井秀始
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Trans-Omics Analysis Shows Novel Functional Change in the Ornithine Metabolic Pathway Between Cancer Stem Cells and Non-Cancer Stem Cells (2016)
  • Author(s): Koseki, J., Matsui, H., Konno, M., Nishida, N., Kawamoto, K., Kano, Y., Asai, A., Doki, Y., Mori, M., Ishii, H.
  • Organizer: The 26th Hot Spring Harbor International Symposium
  • Place of Presentation: Kyushu University(福岡）
  • Year and Date: 2016-11-02 – 2016-11-03
  • Int'l Joint Research / Invited
• [Presentation] Trans-omics Analysis brings out Novel Functions of the Ornithine Metabolic Pathway in Cancer Stem Cells (2016)
  • Author(s): 小関 準, 今野 雅允, 西田 尚弘, 川本 弘一, 土岐 祐一郎, 森 正樹, 石井 秀始
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川）
  • Year and Date: 2016-10-06 – 2016-10-08
  • Int'l Joint Research
• [Presentation] トランスオミックス解析により見い出された癌幹細胞におけるオルニチン代謝経路の新機能 (2016)
  • Author(s): 小関 準
  • Organizer: 第3回次世代がんインフォマティクス研究会
  • Place of Presentation: 岡山大学（岡山）
  • Year and Date: 2016-06-03 – 2016-06-03
• [Presentation] Thermodynamic and molecular orbital analysis of the effects caused by incorporation of novel anti-tumor agent Trifluridine to DNA (2016)
  • Author(s): Koseki, J., Tsunekuni, K., konno, M., Nishida, N., Kawamoto, K., Doki, Y., Mori, M., Ishii, H.
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: Ernest N. Morial Convention Center(アメリカ）
  • Year and Date: 2016-04-16 – 2016-04-20
  • Int'l Joint Research