Novel Aberrant Complexes Induced by EZH2 Overexpression

• Project/Area Number: 19K07661
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Nagoya University
• Principal Investigator: Shinjo Keiko 名古屋大学, 医学系研究科, 講師 (40641618)
• Project Period (FY): 2019-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: EZH2 / 複合体 / 新規複合体

Outline of Research at the Start

EZH2はヒストンメチル化酵素であり、EZH2の発現亢進は多くのがんで観察される。近年EZH2の酵素活性を阻害する薬の開発が進んでいるが、EZH2酵素活性阻害薬は、EZH2が過剰発現した腫瘍のすべてで有効ではなく、EZH2の本来の酵素活性に非依存的な発がんへの関与が注目されている。本研究では我々が見出したEZH2の新規複合体の解明を試みる。この新規複合体はEZH2高発現による悪性化の原因解明につながると考える。さらに新規複合体形成を阻害することは新たな治療標的となりうる。本研究により、EZH2高発現の腫瘍における新たな分子メカニズムの解明が可能であると考える。

Outline of Final Research Achievements

We have previously found that EZH2 forms a complex with histone modification enzyme X (protein X) in several tumor cells overexpressing EZH2. This novel
EZH2 complex may acquire a new function that is different from that of the normal complex and may contribute to malignant transformation. Immunoprecipitation revealed that the EZH2-protein X aberrant complex is also found in the nucleus, although EZH2 localizes mostly in the nucleus. The presence of the EZH2-protein X complex was confirmed by immunoprecipitation. The presence of the complex was also confirmed by a proximity ligation assay (PLA). When PLA reactions were performed on multiple cells, PLA spots showing the complex tended to be more abundant in cancer cells. This binding was also confirmed by FRET. We plan to perform chromatin immunoprecipitation to identify the target gene sites by this complex in the future.

Academic Significance and Societal Importance of the Research Achievements

EZH2は多くの腫瘍で高発現しているが、EZH2が過剰発現した腫瘍のすべてでEZH2阻害剤が有効ではない。このような腫瘍において、EZH2の新たな機序を同定することで新たな治療薬の開発につなげることができる。

Research Products

• [Journal Article] Investigator-initiated phase I trial of an oligonucleotide therapeutic targeting long noncoding RNA TUG 1 for recurrent glioblastoma (2025)
  • Author(s): Deguchi Shoichi、Ohka Fumiharu、Shiba Yoshiki、Yamaguchi Junya、Sato Aya、Shinjo Keiko、Arakawa Yoshiki、Narita Yoshitaka、Kondo Yutaka、Saito Ryuta
  • Journal Title: BMC Cancer Volume: 25 Issue: 1 Pages: 251-251
  • DOI: 10.1186/s12885-025-13623-0
  • Peer Reviewed / Open Access
• [Journal Article] Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR. (2024)
  • Author(s): Ishibashi Kojiro、Ichinose Toshiya、Kadokawa Riki、Mizutani Ryo、Iwabuchi Sadahiro、Togi Sumihito、Ura Hiroki、Tange Shoichiro、Shinjo Keiko、Nakayama Jun、Nanjo Shigeki、Niida Yo、Kondo Yutaka、Hashimoto Shinichi、Sahai Erik、Yano Seiji、Nakada Mitsutoshi、Hirata Eishu.
  • Journal Title: Developmental Cell Volume: 59 Issue: 5 Pages: 579-594
  • DOI: 10.1016/j.devcel.2024.01.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mutation of the SWI/SNF complex component Smarce1 decreases nucleosome stability in embryonic stem cells and impairs differentiation (2024)
  • Author(s): Kashiwagi Katsunobu、Yoshida Junko、Kimura Hiroshi、Shinjo Keiko、Kondo Yutaka、Horie Kyoji
  • Journal Title: Journal of Cell Science Volume: 137 Issue: 6
  • DOI: 10.1242/jcs.260467
  • Peer Reviewed / Open Access
• [Journal Article] Long noncoding RNA TUG1 promotes cisplatin resistance in ovarian cancer via upregulation of DNA polymerase eta (2024)
  • Author(s): Sonobe Ryosuke、Yang Peng、Suzuki Miho M.、Shinjo Keiko、Iijima Kenta、Nishiyama Nobuhiro、Miyata Kanjiro、Kataoka Kazunori、Kajiyama Hiroaki、Kondo Yutaka
  • Journal Title: Cancer Science Volume: 00 Issue: 6 Pages: 1-14
  • DOI: 10.1111/cas.16150
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel pharmacologic inhibition of lysine-specific demethylase 1 as a potential therapeutic for glioblastoma (2024)
  • Author(s): Shinjo Keiko、Umehara Takashi、Niwa Hideaki、Sato Shin、Katsushima Keisuke、Sato Shinya、Wang Xingxing、Murofushi Yoshiteru、Suzuki Miho M.、Koyama Hiroo、Kondo Yutaka
  • Journal Title: Cancer Gene Therapy Volume: 31 Issue: 12 Pages: 1884-1894
  • DOI: 10.1038/s41417-024-00847-8
  • Peer Reviewed
• [Journal Article] Exclusive expression of KANK4 promotes myofibroblast mobility in keloid tissues. (2024)
  • Author(s): Oishi M, Shinjo K, Takanari K, Muraoka A, Suzuki MM, Kanbe M, Higuchi S, Ebisawa K, Hashikawa K, Kamei Y, Kondo Y.
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 8725-8725
  • DOI: 10.1038/s41598-024-59293-z
  • Peer Reviewed / Open Access
• [Journal Article] Rapid detection of the MYD88 L265P mutation for pre‐and intra‐operative diagnosis of primary central nervous system lymphoma. (2023)
  • Author(s): Yamaguchi Junya、Ohka Fumiharu、Kitano Yotaro、Maeda Sachi、Motomura Kazuya、Aoki Kosuke、Takeuchi Kazuhito、Nagata Yuichi、Hattori Hikaru、Tsujiuchi Takashi、Motomura Ayako、Nishikawa Tomohide、Kibe Yuji、Shinjo Keiko、Kondo Yutaka、Saito Ryuta.
  • Journal Title: Cancer Science Volume: - Issue: 6 Pages: 2544-2551
  • DOI: 10.1111/cas.15762
  • Peer Reviewed
• [Journal Article] Mutation detection of urinary cell-free DNA via catch-and-release isolation on nanowires for liquid biopsy (2023)
  • Author(s): Takahashi Hiromi、Yasui Takao、Hirano Masaki、Shinjo Keiko、Miyazaki Yusuke、Shinoda Wataru、Hasegawa Takeshi、Natsume Atsushi、Kitano Yotaro、Ida Mikiko、Zhang Min、Shimada Taisuke、Paisrisarn Piyawan、Zhu Zetao、Ohka Fumiharu、Aoki Kosuke、Rahong Sakon、Nagashima Kazuki、Yanagida Takeshi、Baba Yoshinobu
  • Journal Title: Biosensors and Bioelectronics Volume: 234 Pages: 115318-115318
  • DOI: 10.1016/j.bios.2023.115318
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts. (2023)
  • Author(s): Muraoka Ayako、Suzuki Miho、Hamaguchi Tomonari、Watanabe Shinya、Iijima Kenta、Murofushi Yoshiteru、Shinjo Keiko、Osuka Satoko、Hariyama Yumi、Ito Mikako、Ohno Kinji、Kiyono Tohru、Kyo Satoru、Iwase Akira、Kikkawa Fumitaka、Kajiyama Hiroaki、Kondo Yutaka.
  • Journal Title: Science Translational Medicine Volume: 15 Issue: 700 Pages: 700-700
  • DOI: 10.1126/scitranslmed.add1531
  • Peer Reviewed / Open Access
• [Journal Article] TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation. (2023)
  • Author(s): Suzuki Miho M.、Iijima Kenta、Ogami Koichi、Shinjo Keiko、Murofushi Yoshiteru、Xie Jingqi、Wang Xuebing、Kitano Yotaro、Mamiya Akira、Kibe Yuji、Nishimura Tatsunori、Ohka Fumiharu、Saito Ryuta、Sato Shinya、Kobayashi Junya、Yao Ryoji、Miyata Kanjiro、Kataoka Kazunori、Suzuki Hiroshi I.、Kondo Yutaka.
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 4521-4521
  • DOI: 10.1038/s41467-023-40243-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characteristic DNA methylation profiles of chorionic villi in recurrent miscarriage (2022)
  • Author(s): Matsumoto Y, Shinjo K, Mase S, Fukuyo M, Aoki K, Ozawa F, Yoshihara H, Goto S, Kitaori T, Ozaki Y, Takahashi S, Kaneda A, Sugiura-Ogasawara M, Kondo Y.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 11673-11673
  • DOI: 10.1038/s41598-022-15656-y
  • Peer Reviewed / Open Access
• [Journal Article] CA19-9 in Combination with Methylated HOXA1 and SST Is Useful to Diagnose Stage I Pancreatic Cancer (2022)
  • Author(s): Suehiro Yutaka、Suenaga Shigeyuki、Kunimune Yuki、Yada Shoko、Hamamoto Kaori、Tsuyama Takanori、Amano Shogo、Matsui Hiroto、Higaki Shingo、Fujii Ikuei、Suzuki Chieko、Hoshida Tomomi、Matsumoto Toshihiko、Fujimoto Yuko、Kaino Seiji、Shinjo Keiko、Kondo Yutaka、Sakaida Isao、Takami Taro、Nagano Hiroaki、Yamasaki Takahiro
  • Journal Title: Oncology Volume: 100 Issue: 12 Pages: 674-684
  • DOI: 10.1159/000527342
  • Peer Reviewed
• [Journal Article] Pathogenic Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type Diffuse Astrocytic Gliomas. (2019)
  • Author(s): Ohka F, Shinjo K, Deguchi S, Matsui Y, Okuno Y, Katsushima K, Suzuki M, Kato A, Ogiso N, Yamamichi A, Aoki K, Suzuki H, Sato S, Arul Rayan N, Prabhakar S, Goke J, Shimamura T, Maruyama R, Takahashi S, Suzumura A, Kimura H, Wakabayashi T, Zong H, Natsume A, Kondo Y
  • Journal Title: Cancer Research Volume: 79 Pages: 4814-4827
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Uncovering the diversity of pancreatic cancer-associated fibroblasts (2025)
  • Author(s): Keiko Shinjo, Xingxing Wang, Kohei Kumegawa, Reo Maruyama, Shinji Mii, Yoshiteru Murofushi, Miho Suzuki, Atsushi Enomoto and Yutaka Kondo
  • Organizer: The 13th AACR-JCA Joint Conference in Hawaii
  • Int'l Joint Research
• [Presentation] 新規LSD1阻害剤の開発と脳腫瘍治療への応用 (2024)
  • Author(s): 新城恵子、梅原崇史、丹羽英明、佐藤心、勝島啓佑、佐藤慎哉、汪星星、室伏善照、鈴木美穂、小山裕雄、近藤豊
  • Organizer: 第17回エピジェネティクス研究会年会
• [Presentation] The diversity of cancer-associated fibroblasts in pancreatic cancer (2024)
  • Author(s): Keiko Shinjo, Xingxing Wang, Kohei Kumegawa, Reo Maruyama, Shinji Mii, Yoshiteru Murofushi, Miho Suzuki, Atsushi Enomoto, Yutaka Kondo
  • Organizer: The Eight JCA-AACR Special Joint conference
  • Int'l Joint Research
• [Presentation] マルチオミクス解析による膵臓がんにおけるがん関連線維芽細胞の多様性の解明 (2024)
  • Author(s): 新城恵子、汪星星、粂川昂平、丸山玲緒、三井伸二、室伏善照、鈴木美穂、榎本 篤、近藤 豊
  • Organizer: 第83回日本癌学会学術総会
• [Presentation] 膵臓がんにおけるがん線維芽細胞のエピゲノム不均一性 (2024)
  • Author(s): 新城恵子、汪星星、粂川昂平、丸山玲緒、三井伸二、室伏善照、鈴木美穂、榎本 篤、近藤 豊
  • Organizer: 第47回日本分子生物学会年会
• [Presentation] Integrated Multiomics Analysis revealed the Significance of Transgelin in Driving Pancreatic Cancer-Associated Fibroblast-Mediated Cancer Progression (2024)
  • Author(s): Keiko Shinjo, Xingxing Wang, Kohei Kumegawa, Reo Maruyama, Shinji Mii, Yoshiteru Murofushi, Miho Suzuki, Atsushi Enomoto, Yutaka Kondo
  • Organizer: 2024 American Association for Cancer Research Annual Meeting
  • Int'l Joint Research
• [Presentation] 新規LSD1阻害剤の開発と脳腫瘍に対する治療効果 (2023)
  • Author(s): 新城恵子、梅原崇史、鈴木美穂、近藤 豊
  • Organizer: 第16回エピジェネティクス研究会年会
• [Presentation] LSD1を標的とした脳腫瘍の新規治療薬の開発 (2023)
  • Author(s): 新城恵子、梅原崇史、近藤 豊
  • Organizer: 第27回分子標的治療学会学術集会
• [Presentation] 脳腫瘍を標的とした新規LSD1阻害剤の開発 (2023)
  • Author(s): 新城恵子、梅原崇史、室伏 善照、鈴木美穂、近藤 豊
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] 新規LSD1阻害剤の開発と脳腫瘍に対する治療効果 (2022)
  • Author(s): 新城恵子、梅原崇史、鈴木美穂、柏木克信、近藤 豊
  • Organizer: 第15回エピジェネティクス研究会年会
• [Presentation] 脳腫瘍に対する新規LSD1阻害剤の治療効果 (2022)
  • Author(s): 新城恵子
  • Organizer: 第26回分子標的治療学会学術集会
• [Presentation] 脳腫瘍を標的とした新規LSD1阻害剤の開発とその機序の解明 (2022)
  • Author(s): 新城恵子、梅原崇史、室伏 善照、鈴木美穂、近藤 豊
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] がんエピジェネティクスの新展開 (2022)
  • Author(s): 新城恵子
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] ヒストンメチル化酵素EZH2過剰発現細胞における新規複合体の同定 (2020)
  • Author(s): 新城恵子
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] A Novel EZH2 Complex in Cancer cells (2020)
  • Author(s): 新城恵子
  • Organizer: 15th Asia Epigenome Meeting 2021
  • Int'l Joint Research
• [Book] がんゲノムペディア“エピゲノム創薬” (2024)
  • Author(s): 新城恵子、近藤豊
  • Total Pages: 254
  • Publisher: 羊土社
  • ISBN: 9784758121309
• [Book] 遺伝を考える“エピジェネティクス” (2023)
  • Author(s): 新城恵子、近藤豊
  • Total Pages: 309
  • Publisher: 日本医師会雑誌
• [Book] 胆と膵 (2023)
  • Author(s): 新城恵子、近藤豊
  • Total Pages: 101
  • Publisher: 医学図書出版
  • ISBN: 9784865175400
• [Book] リアルタイム・デジタルPCR実験スタンダード (2022)
  • Author(s): 新城恵子、近藤豊
  • Total Pages: 299
  • Publisher: 羊土社
  • ISBN: 9784758122573
• [Book] 疾患原因遺伝子・タンパク質の解析技術と創薬/診断技術への応用 (2022)
  • Author(s): 新城恵子、近藤豊
  • Total Pages: 530
  • Publisher: 技術情報協会
• [Book] 論文図表を読む作法 (2022)
  • Author(s): 新城恵子、近藤豊
  • Total Pages: 286
  • Publisher: 羊土社
  • ISBN: 9784758122603
• [Book] 疾患原因遺伝子・タンパク質の解析技術と創薬/診断技術への応用 (2022)
  • Author(s): 新城恵子、近藤 豊
  • Total Pages: 9
  • Publisher: 技術情報協会
  • ISBN: 9784861048777
• [Remarks] 名古屋大学腫瘍生物学ホームページ
  • URL: https://www.med.nagoya-u.ac.jp/cancerbio/index.html