Significance of histone methylation in liver carcinogenesis and its possibility as therapeutic target

• Project/Area Number: 18K15741
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Nakatsuka Takuma 東京大学, 医学部附属病院, 助教 (50772042)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: エピゲノム異常 / 肝癌 / ヒストン修飾 / DNA損傷 / アポトーシス / G9a / エピジェネティクス / 肝発がん / ヒストンメチル化修飾

Outline of Final Research Achievements

Histone methyltransferase G9a is involved in various biological functions and diseases. Using liver-specific G9a-deficient mice, we found that hepatocarcinogenesis is suppressed in G9a-knockout livers. As a result of comprehensive gene expression analysis and chromatin immunoprecipitation using mouse liver, we found that G9a contributes to the induction of apoptosis in DNA-damaged hepatocytes through the regulation of p53 target gene expression. Inhibition of G9a attenuates liver carcinogenesis from DNA-damaged hepatocytes and is expected to be a therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

肝癌は難治癌のひとつであり、特に進行肝癌に対しては未だ有効な治療薬が少なく新規治療法の開発が望まれている。慢性肝炎により誘導されるエピゲノム異常が肝発癌に重要な役割を担うことが知られてきているが、本研究の成果により、エピゲノム修飾因子のひとつであるヒストンメチル化酵素G9aがDNA損傷からの肝発癌に重要な役割を担うことが明らかとなった。G9a阻害剤により肝癌発生を抑制できる可能性があり、肝癌に対する新規創薬のターゲットとなることが期待される。

Research Products

• [Journal Article] Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis (2021)
  • Author(s): Takuma Nakatsuka, Keisuke Tateishi*, Hiroyuki Kato, Hiroaki Fujiwara, Keisuke Yamamoto, Yotaro Kudo, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Tsuneo Ikenoue, Takeaki Ishizawa, Kiyoshi Hasegawa, Makoto Tachibana, Yoichi Shinkai, Kazuhiko Koike
  • Journal Title: Cell Death and Disease Volume: 12 Issue: 1 Pages: 99111-99111
  • DOI: 10.1038/s41419-020-03381-1
  • Peer Reviewed / Open Access
• [Presentation] ヒストンメチル化酵素G9aは肝細胞のp53依存性DNA損傷応答と発癌に関与する (2019)
  • Author(s): 中塚拓馬
  • Organizer: 第55回肝臓学会総会
• [Presentation] Histone methyltransferase G9a promotes hepatocarcinogenesis by regulating p53 transactivity during DNA damage response (2018)
  • Author(s): 中塚拓馬
  • Organizer: AASLD The Liver Meeting 2018
  • Int'l Joint Research