Identification of regulatory system for cancer stemness and pplication to cancer therapeutics.

• Project/Area Number: 23701063
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: TANIGUCHI Hiroaki 東京大学, 医科学研究所, 特任准教授 (90563289)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 幹細胞 / 遺伝子 / 癌 / トランスレーショナルリサーチ / 発生・分化 / ヒストンメチル化酵素 / EZH2遺伝子 / KLF2遺伝子 / 癌幹細胞

Research Abstract

Methylation events driven by histone methyltransferases have been implicated in gene silencing and carcinogenesis. We focused on histone methyltransferases related to cancer stemness. In this project, we show that epigenetic silencing of KLF2 occurs in cancer cells through direct transcriptional repression mediated by the histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2). The transfection of KLF2 in cells with EZH2-associated silencing showed a significant anti-tumoral effect, both in culture and in xenografted nude mice. Most importantly, the translation of the described results to human primary samples demonstrated that patients with prostate or breast tumors with low levels of KLF2 and high expression of EZH2 had a shorter overall survival. Moreover, KLF2 regulates stemness phenotype for cancer cells. Finally, we find a low molecular weight compound, which induces KLF2 gene expression using cell-based high-throughput screening system.

Research Products

• [Journal Article] Silencing of theKruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer (2012)
  • Author(s): Taniguchi H, Jacinto F.V., Villanueva A, Fernandez AF, Yamamoto H, Carmona F.J, Puertas S, Marquez VE, Shinomura Y, Imai K, and Esteller M.
  • Journal Title: Oncogene Volume: 31 Pages: 1988-1994
• [Journal Article] Silencing of the Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer (2012)
  • Author(s): Taniguchi H, Jacinto F.V., Villanueva A, Fernandez AF, Yamamoto H, Carmona F.J, Puertas S, Marquez VE, Shinomura Y, Imai K, and Esteller M
  • Journal Title: Oncogene Volume: 31 Issue: 15 Pages: 1988-1994
  • DOI: 10.1038/onc.2011.387
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers. (2012)
  • Author(s): Ohashi H
  • Journal Title: Cancer Sci Volume: 103 Issue: 2 Pages: 252-261
  • DOI: 10.1111/j.1349-7006.2011.02138.x
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeuticactivity in biliary tract cancers. (2011)
  • Author(s): Ohashi H, Adachi Y, Yamamoto H, Taniguchi H, Nosho K, Suzuki H, Arimura Y, Imai K, Carbone DP, Shinomura Y.
  • Journal Title: Cancer Sci Volume: 103(2) Pages: 252-61
• [Journal Article] Shinomura Y. The Efficacy ofIGF-I Receptor Monoclonal Antibody against Human Gastrointestinal Carcinomas is Independent of k-ras Mutation Status. (2011)
  • Author(s): Ii M, Li H, Adachi Y, Yamamoto H, Ohashi H, Taniguchi H, Arimura Y, Carbone DP, Imai K
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 5048-5059
• [Journal Article] Shinomura Y . Co-expression of laminin ss3 and γ2 chains and epigenetic inactivationof laminin α3 chain in gastric cancer (2011)
  • Author(s): Ii M, Yamamoto H, Taniguchi H, Adachi Y, Nakazawa M, Ohashi H, Tanuma T,Sukawa Y, Suzuki H, Sasaki S, Imai K
  • Journal Title: Int J Oncol Volume: 39 Pages: 593-599
• [Journal Article] Sanchez-Cespedes M, Villanueva A, Carmona J, Sanchez-Mut JV, Berdasco M, Moreno V, Capella G, Monk D, Ballestar E, Ropero S, Martinez R, Sanchez-Carbayo M, Prosper F, Agirre X, Fraga MF, Grana O, Perez-Jurado L, Mora J, Puig S, Prat J, Badimon L, Puca AA, Meltzer SJ, Lengauer T, Bridgewater J,Bock C, Esteller M. A DNA methylation fingerprint of 1628 human samples (2011)
  • Author(s): Fernandez AF, Assenov Y, Martin-SuberoJI, Balint B, Siebert R, Taniguchi H, Yamamoto H, Hidalgo M, Tan AC, Galm O, Ferrer I
  • Journal Title: Genome Res Volume: 22(2) Pages: 407-19
• [Journal Article] Shinomura Y. Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis (2011)
  • Author(s): Hizaki K, Yamamoto H, Taniguchi H, Adachi Y, Nakazawa M, Tanuma T, Kato N, Sukawa Y, Sanchez JV, Suzuki H, Sasaki S, Imai K
  • Journal Title: Mod Pathol Volume: 24 Pages: 876-884
• [Journal Article] A DNA methylation fingerprint of 1628 human samples (2011)
  • Author(s): Fernandez AF, Assenov Y, Martin-Subero JI, Balint B, Siebert R, Taniguchi H, Yamamoto H, Hidalgo M, Tan AC, Galm O, Ferrer I, Sanchez-Cespedes M, Villanueva A, Carmona J, Sanchez-Mut JV, Berdasco M, Moreno V, Capella G, Monk D, Ballestar E, Ropero S, Martinez R, Sanchez-Carbayo M, Prosper F, Agirre X, Fraga MF, Grana O, Perez-Jurado L, Mora J, Puig S, Prat J, Badimon L, Puca AA, Meltzer SJ, Lengauer T, Bridgewater J, Bock C, Esteller M
  • Journal Title: Genome Res Volume: 22(2) Issue: 2 Pages: 407-19
  • DOI: 10.1101/gr.119867.110
  • Peer Reviewed
• [Presentation] Brush border Myosin Ia inactivation in gastric tumors and its clinical application (2012)
  • Organizer: 第71回 日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer (2012)
  • Organizer: 第21回がん転移学会総会
  • Place of Presentation: 広島
  • Year and Date: 2012-07-12
• [Presentation] 悪性腫瘍におけるヒストンメチル基転 移酵素 EZH2 による KLF2 の発現抑制とそ の臨床応用 (2011)
  • Organizer: 第62回 日本電気泳動学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-11-13
• [Presentation] ヒト腫瘍におけるヒストンメチル基転移酵素EZH2によるKruppel-likefactor2の転写抑制 (2011)
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] 悪性腫瘍におけるヒストンメチル基転移酵素EZH2によるKLF2の発現抑制とその臨床応用(優秀演題賞) (2011)
  • Organizer: 第20回日本癌病態治療研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-18
• [Book] 固形がんの免疫・抗体療法-基礎研究の進歩と臨床応用-抗体療法の基礎(種類、特徴など)概論 日本臨床 70 巻 12 号 (2012)
  • Author(s): 谷口博昭 、今井浩三
• [Book] DDS を利用した抗 体医薬の展望 ドラッグデリバリーシステムの新展開 II - 核酸医薬・抗体医薬・ワクチ ン医療を支える DDS 技術- (2012)
  • Author(s): 谷口博昭 、今井浩三
  • Publisher: シーエムシー 出版
• [Book] 分子標 的薬-がんから他疾患までの治癒をめざ して-分子標的薬の作用機序・薬理作用- がん浸潤とその抑制日本臨床増刊号 (2012)
  • Author(s): 星野大輔、谷口博昭、越川直彦
• [Remarks] 抗体・ワクチン・分子標的寄付研究部門ホームページにて本研究内容に関しても研究内容に関して一般公開している。
  • URL: http://www.avmr.org/