Establishment of a platform for development of tumor treatment seeds targeting a novel transcription elongation regulator Med26

• Project/Area Number: 17K19578
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Yokohama City University
• Principal Investigator: Takahashi Hidehisa 横浜市立大学, 医学研究科, 教授 (30423544)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 遺伝子発現制御 / 転写 / 腫瘍性疾患 / 抗腫瘍剤 / 転写制御 / 転写伸長 / 創薬 / RNAポリメラーゼII / 腫瘍

Outline of Final Research Achievements

The purpose of this study is to identify compounds that inhibit the binding between Med26 and SEC, and to develop anti-neoplastic drugs that suppress the growth of cancer cells and acute leukemia cells. Med26 binds SEC through its N-terminal domain (NTD) and promotes the expression of tumor-associated genes.
In this study, we found that GAL4-Med26-NTD, in which the DNA binding domain of the yeast transcription factor GAL4 was fused to the NTD of Med26, exerts inrinsic transcription activity in cells by binding to SEC. Therefore, in this study, we generated cell line that stably expresses GAL4-Med26-NTD and detects de novo transcription.

Academic Significance and Societal Importance of the Research Achievements

転写伸長因子P-TEFbをリクルートするBRD4の阻害剤JQ1は、強い抗腫瘍効果を発揮することから世界的に注目されている。Med26の阻害剤は、SEC（2つの転写伸長因子P-TEFbとELL/EAF）のリクルートを阻害することから、得られる可能性のある化合物はJQ1よりも強い抗腫瘍効果を発揮することが期待される。

Research Products

• [Int'l Joint Research] Stowers Institute for Medical Research(米国)
• [Journal Article] Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous Cell Carcinoma. (2018)
  • Author(s): Yanagi T, Watanabe M, Hata H, Kitamura S, Imafuku K, Yanagi H, Homma A, Wang L, Takahashi H, Shimizu H, Hatakeyama S.
  • Journal Title: Cancer Res Volume: 78 Issue: 24 Pages: 6795-6806
  • DOI: 10.1158/0008-5472.can-18-1495
  • Peer Reviewed
• [Journal Article] Anti-Sez6l2 antibody, detected in a patient with immune-mediated cerebellar ataxia, inhibits complex formation of GluR1 and Sez6l2 (2018)
  • Author(s): Yaguchi, H., Yabe, I., Takahashi, H., Watanabe, M., Nomura, T., Kano, T., Watanabe, M. and Hatakeyama, S.
  • Journal Title: J. Neurol. Volume: 265 Issue: 4 Pages: 962-965
  • DOI: 10.1007/s00415-018-8785-z
  • Peer Reviewed
• [Journal Article] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 819-819
  • DOI: 10.1038/s41598-018-19198-0
  • NAID: 120006377499
  • Peer Reviewed / Open Access
• [Journal Article] Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure (2018)
  • Author(s): Matsumoto Junichi、et al. Hatakeyama Shigetsugu、Matsumoto Masaki、Nakayama Keiichi I.、Otsuka Yutaro、Sabe Hisataka、Tsutsui Hiroyuki、Anzai Toshihisa
  • Journal Title: Circulation Volume: 138 Issue: 18 Pages: 2064-2066
  • DOI: 10.1161/circulationaha.118.035212
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sez6l2 regulates phosphorylation of ADD and neuritogenesis (2017)
  • Author(s): Yaguchi, H., Yabe, I., Takahashi, H., Watanabe, M., Nomura, T., Kano, T., Matsumoto, M., Nakayama, K.I., Watanabe, M. and Hatakeyama, S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 494 Issue: 1-2 Pages: 234-241
  • DOI: 10.1016/j.bbrc.2017.10.047
  • Peer Reviewed
• [Presentation] The role of Mediator in transcription termination. (2018)
  • Author(s): Takahashi H, Amol Ranjan, Shiyuan Chen, Shibata M, Takigawa I, Watanabe M, Tsukiyama T, Fujii S, Yamamoto J, Yamaguchi Y, Matsumoto M, Nakayama K, Suzuki Y, Sato C, Sato S, Ronald C. Conaway, Joan W. Conaway, Hatakeyama S:
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] メディエーター複合体のサブユニットMED26による転写制御機構 (2018)
  • Author(s): 高橋 秀尚
  • Organizer: 第12回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] Human Mediator subunit MED26 plays a role in 3’-end processing of replication dependent Histone mRNA through recruitment of little elongation complex (2017)
  • Author(s): Hidehisa Takahashi, Mio Shibata, Ichigaku Takigawa, Masashi Watanabe, Junichi Yamamoto, Yuki Yamaguchi, Joan W. Conaway, Ronald C. Conaway, Shigetsugu Hatakeyama
  • Organizer: CSHL meeting on Mechanisms of Eukaryotic Transcription, Cold Spring Harbor Laboratory
  • Int'l Joint Research
• [Presentation] メディエーター複合体による転写終結制御機構 (2017)
  • Author(s): 高橋秀尚，柴田美音，瀧川一学，渡部昌，築山忠維，藤井聡，飯田緑，山本淳一，山口雄輝，Amol Ranjan，Shigeo Sato，Chieri-tomomori Sato，Joan W. Conaway，Ronald C. Conaway，畠山鎮次
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Remarks] 横浜市立大学・大学院医学研究科・分子細胞生物学教室
  • URL: https://ycu-molecularbiology.jp/