Posttranscriptional mechanism of Hippo pathway regulation

• Project/Area Number: 20K07590
• 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: Kobe University
• Principal Investigator: Otani Junji 神戸大学, 医学研究科, 助教 (10770878)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Hippo経路 / 翻訳 / Hippo / YAP

Outline of Research at the Start

多種類のがんで転写共役因子YAP/TAZの異常な活性化が認められ、その活性を抑制するHippo経路の構成因子欠損マウスにおいて、種々のがんが早期から高率に発症することから、Hippo-YAP経路のがんの発症、進展における役割に注目が集まっている。本研究では、ゲノムワイドsiRNAスクリーニングにより、YAP依存的な遺伝子転写活性に強力に作用する薬剤標的分子を同定し、YAP活性を標的とした抗腫瘍薬の開発に貢献することを目指す。

Outline of Final Research Achievements

This study aims to identify novel drug targets to inhibit the activation of the transcription coactivators YAP and transcription factor TEAD, which promote cancer cell growth. Whole genome siRNA library screening was performed using cell lines with high sensitivity for the activity of oncogenic gene transcription by YAP-TEAD. The results revealed that RNABP, a post-transcriptional regulator of mRNA, potently activates the transcriptional activity of YAP-TEAD and contributes to cancer cell proliferation, invasion, and migration. RNABP activates YAP-TEAD by suppressing the expression of VGLL4, a YAP inhibitor.

Academic Significance and Societal Importance of the Research Achievements

Hippo-YAP経路は、がんの重要なドライバー経路であることが明らかになりつつある。本研究では1分子の発現抑制により最も強くYAP-TEADによる転写活性を阻害する遺伝子を同定し、そのYAP-TEADへの作用機序の解明、阻害剤開発によって癌撲滅に貢献することを目指したものである。本研究から、mRNAの転写後調節機構が細胞の運命決定に重要な役割を持っていることが明らかになった。

Research Products

• [Journal Article] Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers. (2022)
  • Author(s): Soyama H, Nishio M, Otani J, Sakuma T, Takao S, Hara S, Masuda T, Mimori K, Toyokuni S, Lydon JP, Nakao K, Nishina H, Fukumoto T, Maehama T, Suzuki A.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 119 Issue: 29 Pages: 1-10
  • DOI: 10.1073/pnas.2123134119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine inhibits bladder cancer progression by suppressing YAP1/TAZ (2022)
  • Author(s): Shiraishi Y, Maehama T, Nishio M, Otani J, Hikasa H, Mak TW, Sasaki T, Honma T, Kondoh Y, Osada H, Yoshida M, Fujisawa M, Suzuki A.
  • Journal Title: Genes Cells Volume: 27(10) Issue: 10 Pages: 602-612
  • DOI: 10.1111/gtc.12979
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The <i>TIGD5</i> gene located in 8q24 and frequently amplified in ovarian cancers is a tumor suppressor (2022)
  • Author(s): Dai Yuntao、Kawaguchi Tetsuya、Nishio Miki、Otani Junji、Tashiro Hironori、Terai Yoshito、Sasaki Ryohei、Maehama Tomohiko、Suzuki Akira
  • Journal Title: Genes to Cells Volume: 27 Issue: 11 Pages: 633-642
  • DOI: 10.1111/gtc.12980
  • Peer Reviewed / Open Access
• [Journal Article] TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands. (2021)
  • Author(s): Miyachi Y, Nishio M, Otani J, Matsumoto S, Kikuchi A, Mak TW, Maehama T, Suzuki A.
  • Journal Title: Genes Cells. Volume: 26(9) Issue: 9 Pages: 714-726
  • DOI: 10.1111/gtc.12879
  • NAID: 120007148944
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation. (2021)
  • Author(s): Nakatani K, Maehama T, Nishio M, Otani J, Yamaguchi K, Fukumoto M, Hikasa H, Hagiwara S, Nishina H, Mak TW, Honma T, Kondoh Y, Osada H, Yoshida M, Suzuki A
  • Journal Title: Cancer Science Volume: 112 Issue: 10 Pages: 4303-4316
  • DOI: 10.1111/cas.15079
  • NAID: 120007159906
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice. (2020)
  • Author(s): Miki Nishio , Yoko To , Tomohiko Maehama , Yukari Aono , Junji Otani , Hiroki Hikasa , Akihiro Kitagawa , Koshi Mimori , Takehiko Sasaki , Hiroshi Nishina , Shinya Toyokuni , John P Lydon , Kazuwa Nakao , Tak Wah Mak , Tohru Kiyono , Hidetaka Katabuchi , Hironori Tashiro , Akira Suzuki
  • Journal Title: Cancer science Volume: 111 Issue: 10 Pages: 3576-3578
  • DOI: 10.1111/cas.14581
  • NAID: 120006892076
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The role of Hippo-YAP signaling in squamous cell carcinomas. (2020)
  • Author(s): Tomohiko Maehama , Miki Nishio , Junji Otani , Tak Wah Mak , Akira Suzuki
  • Journal Title: Cancer science Volume: 112 Issue: 1 Pages: 51-60
  • DOI: 10.1111/cas.14725
  • NAID: 120006950333
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] がん抑制因子PTENの制御に関わる新たな因子の同定 (2022)
  • Author(s): 池末信太郎、前濱朝彦、西尾美希、大谷淳二、鈴木聡
  • Organizer: 第19回生命科学研究会
• [Presentation] がん抑制因子PTENの制御に関わる新たな因子の同定 (2022)
  • Author(s): 前濱朝彦、池末信太郎、西尾美希、大谷淳二、鈴木聡
  • Organizer: 第95回日本生化学会大会
• [Presentation] Hippo-TAZ signaling is the master regulator for the onset of triple-negative basal-like breast cancers (2022)
  • Author(s): Junji Otani, Hirotoshi Soyama, Miki Nishio, Tomohiko Maehama, Akira Suzuki
  • Organizer: FASEB 2023 The Protein Phosphatases Conference
• [Presentation] 核小体オルガネラゾーンにおけるストレス制御と癌の発症進展機構 (2020)
  • Author(s): 前濱朝彦、大谷淳二、鈴木 聡
  • Organizer: オルガネラゾーン領域会議
• [Presentation] YAP1/TAZ阻害による抗腫瘍作用を示す天然物の同定 (2020)
  • Author(s): 西尾美希、中谷圭佑、大谷淳二、日笠弘基、前濱朝彦、鈴木聡
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] A natural product Alantolactone is a potent YAP1/TAZ inhibitor via ROS production (2020)
  • Author(s): Junji Otani, Keisuke Nakatani, Tomohiko Maehama, Miki Nishio, Akira Suzuki
  • Organizer: The 14th International Conference on Protein Phosphatase
  • Int'l Joint Research
• [Presentation] Hippo-YAP/TAZ経路による肥満の制御 (2020)
  • Author(s): 山口慶子、西尾美希、大谷淳二、前濱朝彦、鈴木聡
  • Organizer: オルガネラゾーン若手の会