The regulatory machinery of histone methyltransferases ESET in normal liver and liver cancer

• Project/Area Number: 25460977
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Chiba University
• Principal Investigator: Chiba Tetsuhiro 千葉大学, 医学(系)研究科(研究院), 講師 (00381583)
• Co-Investigator(Renkei-kenkyūsha): IWAMA ATSUSHI 千葉大学, 大学院医学研究院, 教授 (70244126)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 幹細胞 / ヒストンメチル化酵素 / 肝癌

Outline of Final Research Achievements

Histone lysine methyltransferases, such as ESET and SUV39H1, regulate transcriptional repression through the formation of Histone H3 lysine 9 trimethylation (H3K9me3). In the loss-of-function assays for HCC cells, SUV39H1 knockdown but not ESET knockdown reduced H3K9me3 levels and impaired HCC cell growth and sphere formation. The expression levels of SUV39H1 but not those of ESET were significantly correlated with H3K9me3 levels in primary HCC samples. In addition, loss of ESET function in embryonic murine hepatic stem/progenitor cells derived from tamoxifen-inducible conditional knockout mice for ESET, severely impaired proliferation and self-renewal capability.
Our findings indicate that ESET plays an essential role in the maintenance of both the proliferative and self-renewal capacity of hepatic stem/progenitor cells but not in the tumorigenicity of HCC cells.

Research Products

• [Journal Article] Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology (2016)
  • Author(s): Chiba T, Iwama A, Yokosuka O
  • Journal Title: Hepatol Res Volume: 46 Issue: 1 Pages: 50-57
  • DOI: 10.1111/hepr.12548
  • Peer Reviewed
• [Journal Article] Biological features and biomarkers in hepatocellular carcinoma (2015)
  • Author(s): Chiba T, Suzuki E, Saito T, Ogasawara S, Ooka Y, Tawada A, Iwama A, Yokosuka O
  • Journal Title: World J Hepatol Volume: 7 Issue: 16 Pages: 2020-2028
  • DOI: 10.4254/wjh.v7.i16.2020
  • Peer Reviewed
• [Journal Article] Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma. (2015)
  • Author(s): Chiba T, Saito T, Yuki K, Zen Y, Koide S, Kanogawa N, Motoyama T, Ogasawara S, Suzuki E, Ooka Y, Tawada A, Otsuka M, Miyazaki M, Iwama A, Yokosuka O.
  • Journal Title: Int J Cancer Volume: 136 Issue: 2 Pages: 289-298
  • DOI: 10.1002/ijc.28985
  • Peer Reviewed
• [Journal Article] Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners (2014)
  • Author(s): Chiba T, Suzuki E, Yuki K, Zen Y, Oshima M, Miyagi S, Saraya A, Koide S, Motoyama T, Ogasawara S, Ooka Y, Tawada A, Nakatsura T, Hayashi T, Yamashita T, Kaneko S, Miyazaki M, Iwama A, Yokosuka O
  • Journal Title: PLoS One Volume: 9(1) Issue: 1 Pages: e84807-e84807
  • DOI: 10.1371/journal.pone.0084807
  • Peer Reviewed
• [Journal Article] Metformin, a Diabetes Drug, Eliminates Tumor-Initiating Hepatocellular Carcinoma Cells. (2013)
  • Author(s): Saito, T., Chiba, T., Yuki, K., Zen, Y., Oshima, M., Koide, S., Motoyama, T., Ogasawara, S., Suzuki, E., Ooka, Y., Tawada, A., Tada, M., Kanai, F., Takiguchi, Y., Iwama, A. and Yokosuka, O.
  • Journal Title: PloS one Volume: 8 Issue: 7 Pages: e70010-e70010
  • DOI: 10.1371/journal.pone.0070010
  • Peer Reviewed
• [Presentation] Cancer stem cells in hepatocellular carcinoma and epigenetic therapy (2016)
  • Author(s): Tetsuhiro Chiba
  • Organizer: the Asian Pacific Association for the Study of the Liver (APASL)
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区)
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] ヒストンメチル化による肝幹細胞の分化制御機構の検討 (2015)
  • Author(s): 千葉哲博, 岩間厚志, 横須賀收
  • Organizer: 日本消化器関連学会週間
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区)
  • Year and Date: 2015-10-08