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Targeting novel bromodomain protein in colorectal cancer

Research Project

Project/Area Number 17K07214
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor therapeutics
Research InstitutionThe University of Tokyo

Principal Investigator

Yamaguchi Kiyoshi  東京大学, 医科学研究所, 特任講師 (50466843)

Co-Investigator(Kenkyū-buntansha) 古川 洋一  東京大学, 医科学研究所, 教授 (20272560)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords大腸がん / 分子標的治療 / エピジェネティクス / ブロモドメイン / 遺伝子発現 / 遺伝子発現制御 / ゲノム
Outline of Final Research Achievements

Our recent studies have disclosed that BRD8, a member of bromodomain family proteins, is accumulated in cancer cells, and that BRD8 plays a role in transcriptional events. However, the fundamental function of its bromodomain is largely unknown. In this study, we found that BRD8 interacts with histone protein(s) in cells, and their interactions are insensitive to the BET (bromodomains and extra-terminal domain) inhibitor which targets a bromodomain in BRD4. In addition, we generated BRD8-knockout colorectal cancer cells using CRISPR-Cas9 system, and examined in vitro spheroid formation of the cells. The spheroid formation was significantly suppressed by the knockout of BRD8. Our data suggest that BRD8 might be a novel therapeutic target for colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

アセチル化修飾を受けたタンパク質を認識するブロモドメインは、有望な創薬(druggable)ターゲットである。BRD8はアミノ酸配列の違いから、創薬開発が進んでいるBETファミリー(BRD2、BRD3、BRD4およびBRDT)のブロモドメインとは区別され、その生物学的な役割は不明な点が多かった。これまでの我々の研究成果は、がんの発生や進展におけるBRD8の関与を裏付けるものであり、今後、BRD8のエピジェネティック情報認識機能や転写調節機能を標的(阻害)とする新しい抗がん剤開発への展開が期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (45 results)

All 2020 2019 2018 2017 Other

All Journal Article (15 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 15 results,  Open Access: 10 results,  Acknowledgement Compliant: 1 results) Presentation (29 results) (of which Int'l Joint Research: 7 results) Remarks (1 results)

  • [Journal Article] Discovery of chemical probes that suppress Wnt/β-catenin signaling through high-throughput screening.2020

    • Author(s)
      Yamaguchi K, Nagatoishi S, Tsumoto K, Furukawa Y.
    • Journal Title

      Cancer Sci.

      Volume: 111 Issue: 3 Pages: 783-794

    • DOI

      10.1111/cas.14297

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient2019

    • Author(s)
      Yamaguchi K, Shimizu E, Yamaguchi R, Imoto S, Komura M, Hatakeyama S, Noguchi R, Takane K, Ikenoue T, Gohda Y, Yano H, Miyano S, Furukawa Y
    • Journal Title

      J Hum Genet.

      Volume: 64(8) Issue: 8 Pages: 729-740

    • DOI

      10.1038/s10038-019-0611-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells2019

    • Author(s)
      Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Takane K, Shinozaki M, Tsurita G, Yano H, Furukawa Y
    • Journal Title

      Oncogene

      Volume: 38(32) Issue: 32 Pages: 6051-6064

    • DOI

      10.1038/s41388-019-0856-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Importance of Gastric Cancer for the Diagnosis and Surveillance of Japanese Lynch Syndrome Patients2019

    • Author(s)
      Ikenoue T, Arai M, Ishioka C, Iwama T, Kaneko S, Matsubara N, Moriya Y, Nomizu T, Sugano K, Tamura K, Tomita N, Yoshida T, Sugihara K, Naruse H, Yamaguchi K, Nojima M, Nakamura Y, Furukawa Y; Japanese society for cancer of the colon and rectum (JSCCR)
    • Journal Title

      J Hum Genet.

      Volume: 64 Issue: 12 Pages: 1187-1194

    • DOI

      10.1038/s10038-019-0674-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer.2018

    • Author(s)
      Johmura Y, Maeda I, Suzuki N, Wu W, Goda A,Morita M, Yamaguchi K, Yamamoto M, Nagasawa S, Kojima Y, Tsugawa K, Inoue N, Miyoshi Y, Osako T Akiyama F, Maruyama R, Inoue JI, Fukukawa Y, Ohta T, Nkanishi M.
    • Journal Title

      J Clin Invest.

      Volume: 128 Issue: 12 Pages: 5603-5619

    • DOI

      10.1172/jci121679

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy of liquid-based genetic diagnosis of endometrial cancer.2018

    • Author(s)
      Matsuura M, Yamaguchi K, Tamate M, Satohisa S, Teramoto M, Iwasaki M, Sugita S, Hasegawa T, Koubo R, Takane K, Ikenoue T, Furukawa Y, Saito T.
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 12 Pages: 4025-4032

    • DOI

      10.1111/cas.13819

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of tankyrase activity by a catalytic domain dimer interface2018

    • Author(s)
      Fan Chen、Yarravarapu Nageswari、Chen Hua、Kulak Ozlem、Dasari Pranathi、Herbert Jeremiah、Yamaguchi Kiyoshi、Lum Lawrence、Zhang Xuewu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 503 Issue: 3 Pages: 1780-1785

    • DOI

      10.1016/j.bbrc.2018.07.113

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors2018

    • Author(s)
      Chen Kenneth S.、Fustino Nicholas J.、Shukla Abhay A.、Stroup Emily K.、Budhipramono Albert、Ateek Christina、Stuart Sarai H.、Yamaguchi Kiyoshi、Kapur Payal、Frazier A. Lindsay、Lum Lawrence、Looijenga Leendert H.J.、Laetsch Theodore W.、Rakheja Dinesh、Amatruda James F.
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: 17 Issue: 5 Pages: 1079-1089

    • DOI

      10.1158/1535-7163.mct-17-0137

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation.2018

    • Author(s)
      Ikenoue T, Terakado Y, Zhu C, Liu X, Ohsugi T, Matsubara D, Fujii T, Kakuta S,Kubo S, Shibata T, Yamaguchi K, Iwakura Y, Furukawa Y.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 2021-2021

    • DOI

      10.1038/s41598-018-19769-1

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Decreased expression of interferon-induced protein 2 (IFIT2) by Wnt/β-catenin signaling confers anti-apoptotic properties to colorectal cancer cells.2017

    • Author(s)
      Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Furukawa Y.
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 59 Pages: 100176-100186

    • DOI

      10.18632/oncotarget.22122

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Requirement of glycosylation machinery in TLR responses revealed by CRISPR/Cas9 screening2017

    • Author(s)
      Sato Ryota、Shibata Takuma、Tanaka Yu、Kato Chiharu、Yamaguchi Kiyoshi、Furukawa Yoichi、Shimizu Eigo、Yamaguchi Rui、Imoto Seiya、Miyano Satoru、Miyake Kensuke
    • Journal Title

      International Immunology

      Volume: 29 Issue: 8 Pages: 347-355

    • DOI

      10.1093/intimm/dxx044

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bidirectional reporter assay using HAL promoter and TOPFLASH improves specificity in high-throughput screening of Wnt inhibitors.2017

    • Author(s)
      Yamaguchi K, Zhu C, Ohsugi T, Yamaguchi Y, Ikenoue T, Furukawa Y.
    • Journal Title

      Biotechnology and Bioengineering

      Volume: 114 Issue: 12 Pages: 2868-2882

    • DOI

      10.1002/bit.26394

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic alterations in Japanese extrahepatic biliary tract cancer.2017

    • Author(s)
      Noguchi R, Yamaguchi K, Ikenoue T, Terakado Y, Ohta Y, Yamashita N, Kainuma O, Yokoi S, Maru Y, Nagase H, Furukawa Y.
    • Journal Title

      Oncology Letters

      Volume: 14 Issue: 1 Pages: 877-884

    • DOI

      10.3892/ol.2017.6224

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Altered expression of microRNAs in patients with pouchitis after restorative proctocolectomy2017

    • Author(s)
      Inoue Emi、Hata Keisuke、Kimura Hideaki、Yamaguchi Kiyoshi、Nojima Masanori、Endo Itaru、Shinozaki Masaru
    • Journal Title

      Surgery Today

      Volume: 47 Issue: 12 Pages: 1484-1491

    • DOI

      10.1007/s00595-017-1550-6

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex.2017

    • Author(s)
      Zhu C, Yamaguchi K, Osugi T, Terakado Y, Noguchi R, Ikenoue T, Furukawa Y
    • Journal Title

      Cancer Science

      Volume: 印刷中 Issue: 4 Pages: 612-619

    • DOI

      10.1111/cas.13174

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] ロングリードシーケンスによるリンチ症候群患者のミスマッチ修復遺伝子の構造異常の解析2019

    • Author(s)
      山口 貴世志、笠島 理加、清水 英悟、高根 希世子、池上 恒雄、山口 類、井元 清哉、宮野 悟、古川 洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Wntシグナル経路の新規標的遺伝子odontogenic ameloblast associated (ODAM)の同定2019

    • Author(s)
      堀江 千晶、山口 貴世志、高根 希世子、池上 恒雄、古川 洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 子宮体がんスクリーニングにおける子宮内膜液状化細胞診検体を用いた遺伝子解析の有用性2019

    • Author(s)
      池上 恒雄、松浦 基樹、高根 希世子、山口 貴世志、齋藤 豪、古川 洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CRISPR/Cas9システムを用いたトリプルネガティブ乳癌におけるEMT/MET可塑性制御機構の解析2019

    • Author(s)
      山本 瑞生、山口 貴世志、古川 洋一、井上 純一郎
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 麻疹ウイルス受容体PVRL4はがん細胞においてBACH1により調節される2019

    • Author(s)
      高根 希世子、山口 貴世志、池上 恒雄、藤幸 知子、米田 美佐子、甲斐 知惠子、古川 洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 大腸癌においてWnt /β-カテニンシグナルはインターフェロン制御因子1(IRF1)を制御する2019

    • Author(s)
      大杉 友之、山口 貴世志、池上 恒雄、高根 希世子、篠崎 大、矢野 秀朗、釣田 義一郎、古川 洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Kras活性化とPten欠損に起因するマウス肝内胆管癌における細胞内シグナルの検討2019

    • Author(s)
      劉 洵、池上 恒雄、寺門 侑美、高根 希世子、山口 貴世志、古川 洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CRISPR/Cas9システムを用いたトリプルネガティブ乳癌におけるEMT/MET可塑性制御機構の解析2019

    • Author(s)
      山本 瑞生、山口 貴世志、古川 洋一、井上 純一郎
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The CRISPR/Cas9-mediated gene knockout screening to analyze EMT-MET plasticity in triple-negative breast cancer2019

    • Author(s)
      Mizuki Yamamoto、Kiyoshi Yamaguchi、Yoichi Furukawa、Jun-ichiro Inoue
    • Organizer
      Cell Symposia: Hallmarks of Cancer
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Wnt/β-catenin signaling controls interferon regulatory factor 1 (IRF1) in colorectal cancer cells2019

    • Author(s)
      Kiyoshi Yamaguchi、Tomoyuki Ohsugi、Kiyoko Takane、Tsuneo Ikenoue、Yoichi Furukawa
    • Organizer
      11th AACR-JCA Joint Conference
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Wntシグナルを抑制する物質探索のための新たなスクリーニング戦略2018

    • Author(s)
      山口 貴世志、古川 洋一
    • Organizer
      第9回スクリーニング学研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] Molecular features of colorectal cancer in patient with polymerase proofreading-associated polyposis (PPAP)2018

    • Author(s)
      Kiyoshi Yamaguchi、Eigo Shimizu、Seira Hatakeyama、Rei Noguchi、Tsuneo Ikenoue、Rui Yamaguchi、Seiya Imoto、Satoru Miyano、Yoichi Furukawa
    • Organizer
      The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor International Symposium 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Accurate and Robust Base-calling for Nanopore Raw Reads with Variation of Species Exploiting Neural Machine Translation Model2018

    • Author(s)
      Hiroki Konishi、Rui Yamaguchi、Kiyoshi Yamaguchi、Yoichi Furukawa、Seiya Imoto
    • Organizer
      The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor International Symposium 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 全ゲノム解析により同定されたポリメラーゼ校正関連ポリポーシスの発症に関わる新たなPOLE遺伝子変異2018

    • Author(s)
      山口 貴世志、清水 英悟、上村 光弘、山口 類、井元 清哉、池上 恒雄、宮野 悟、古川 洋一
    • Organizer
      日本人類遺伝学会 第63回大会
    • Related Report
      2018 Research-status Report
  • [Presentation] ポリメラーゼ校正関連ポリポーシス患者由来の大腸腫瘍の遺伝子およびエピゲノム解析2018

    • Author(s)
      山口 貴世志、清水 英悟、池上 恒雄、高根 希世子、山口 類、井元 清哉、宮野 悟、古川 洋一
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Kras活性化とPten不活化による状況依存的なマウス肝腫瘍の誘導2018

    • Author(s)
      池上 恒雄、寺門 侑美、劉 洵、高根 希世子、山口 貴世志、古川 洋一
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 新規FBXW7癌特異的変異条件的ノックインマウスの樹立と解析2018

    • Author(s)
      劉 洵、池上 恒雄、寺門 侑美、朱 赤、大杉 友之、松原 大祐、藤井 智明、角田 茂、久保 幸子、柴田 琢磨、山口 貴世志、岩倉 洋一郎、古川 洋一
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] FAP家系に発症した二卵性双胎肝芽腫2018

    • Author(s)
      西塚 哲、有末 篤弘、高根 希世子、山口 貴世志、朝倉 賀子、平井 大士、遠藤 幹也、水野 大、石田 和之、菅井 有、宮野 悟、古川 洋一
    • Organizer
      第6回日本家族性大腸腺腫症研究会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 子宮内膜液状化細胞診検体による遺伝子解析研究2018

    • Author(s)
      松浦 基樹、玉手 雅人、郷久 晴朗、寺本 瑞絵、幸保 莉香、畠山 晴良、山口 貴世志、杉田 真太朗、池上 恒雄、岩雅 宏、長谷川 匡、古川 洋一、齋藤 豪
    • Organizer
      第59回日本臨床細胞学会春季大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Development of high-specific and sensitive reporter assays for the detection of Wnt/β-catenin signaling activity2018

    • Author(s)
      Kiyoshi Yamaguchi、Chi Zhu、Tomoyuki Ohsugi、Akari Saku、Tsuneo Ikenoue、Yoichi Furukawa
    • Organizer
      American Association for Cancer Research 109th Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Wnt阻害剤開発のための新たな化合物ライブラリスクリーニング戦略2017

    • Author(s)
      山口 貴世志、古川 洋一
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Kras変異とPten欠損に起因する肝内胆管癌発生進展におけるHes1の役割2017

    • Author(s)
      池上 恒雄、寺門 侑美、松原 大祐、山口 貴世志、古川 洋一
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Wntシグナルで制御される分子FRMD5の大腸がんでの発現と役割2017

    • Author(s)
      朱 赤、大杉 友之、寺門 侑美、野口 玲、池上 恒雄、山口 貴世志、古川 洋一
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 病態メカニズム解明のための腹膜偽粘液腫の遺伝子発現解析2017

    • Author(s)
      野口 玲、合田 良政、秀野 泰隆、山口 貴世志、池上 恒雄、猪狩 亨、大田 泰徳、矢野 秀朗、古川 洋一
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Wntシグナル経路は大腸がんにおいてインターフェロン誘導タンパク質を抑制する2017

    • Author(s)
      大杉 友之、山口 貴世志、朱 赤、池上 恒雄、古川 洋一
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 腫瘍溶解性麻疹ウイルスレセプターPVRL4の発現調節機構の解明2017

    • Author(s)
      朔 あかり、山口 貴世志、池上 恒雄、藤幸 知子、米田 美佐子、秦 裕子、尾山 大明、甲斐 知惠子、古川 洋一
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 全ゲノム解析により見つかったFAP患者におけるAPC遺伝子の転写調節異常2017

    • Author(s)
      山口 貴世志、清水 英悟、上村 光弘、長山 聡、山口 類、井元 清哉、池上 恒雄、宮野 悟、古川 洋一
    • Organizer
      第5回日本家族性大腸腺腫症研究会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Identification of FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex2017

    • Author(s)
      Yoichi Furukawa、Chi Zhu、Tomoyuki Ohsugi、Yumi Terakado、Rei Noguchi、Tsuneo Ikenoue、Kiyoshi Yamaguchi
    • Organizer
      American Association for Cancer Research 108th Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Wnt signaling induces anti-apoptotic effect in colorectal cancer cells through the suppression of IFITs2017

    • Author(s)
      Tomoyuki Ohsugi、Kiyoshi Yamaguchi、Chi Zhu、Tsuneo Ikenoue、Yoichi Furukawa
    • Organizer
      American Association for Cancer Research 108th Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Remarks] 東京大学医科学研究所 臨床ゲノム腫瘍学分野

    • URL

      https://www.ims.u-tokyo.ac.jp/furukawa/

    • Related Report
      2019 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2023-12-25  

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