The relationships between radioresistance and polyamine metabolism in cervical cancer stem cell

• Project/Area Number: 16K10393
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Osaka University
• Principal Investigator: Fumiaki Isohashi 大阪大学, 医学系研究科, 特任准教授(常勤) (00448036)
• Co-Investigator(Kenkyū-buntansha): 瀬尾 雄二 大阪大学, 医学系研究科, 助教 (00302000) ; 玉利 慶介 大阪大学, 医学系研究科, 特任助教(常勤) (30718995) ; 小川 和彦 大阪大学, 医学系研究科, 教授 (40253984)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 癌幹細胞 / 放射線治療 / ポリアミン代謝 / 放射線科学 / 放射線腫瘍学

Outline of Final Research Achievements

A method of eradicating a small group "cancer stem cells" among cancer cells that are resistant to radiation and anticancer drugs and have tumorigenicity is considered to be effective for cancer treatment. Radiation resistance of cervical cancer stem cells and differences in polyamine metabolism between cancer stem cells and non-cancer stem cells. ID1 was highly expressed specifically in cancer stem cells, and exposure of polyamines to cell lines also resulted in enhanced expression of ID1. It was revealed that the high polyamine concentration in the cells promotes gene expression of ID1 epigenetically. It was suggested that when the intracellular polyamine concentration is high, it becomes like cancer stem cells that are resistant to radiation treatment.

Academic Significance and Societal Importance of the Research Achievements

放射線や抗癌剤に抵抗性をもち、かつ造腫瘍性をもつ、癌幹細胞を撲滅する方法は癌治療に有効であると考えられるが、癌幹細胞の代謝とエピジェネティクスに関する研究はこれまでになされていなかった。この様な背景の中で、我々は癌幹細胞の細胞内のポリアミン濃度が高いことをまず明らかとし、そのポリアミンが癌幹細胞の維持に重要であることを明らかとした。具体的には癌幹細胞のポリアミン濃度が高いことで、ヒストン脱メチル化酵素であるLSD1が阻害され、癌幹細胞関連遺伝子であるID1 遺伝子プロモーター領域でのヒストンH3K4のメチル化を亢進させ、ID1の遺伝子発現促進に寄与していることが明らかとなった。

Research Products

• [Journal Article] Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells (2018)
  • Author(s): Tamari K, KonnoM , Asai A, Koseki J, Hayashi K, Kawamoto K, Murai N, Matsufuji S, Isohashi F, Satoh T, Gotoh N, Tanaka S, Doki Y, Mori M, Ogawa K, Ishii H.
  • Journal Title: Cell Death Discovery Volume: 4 Issue: 104 Pages: 104-104
  • DOI: 10.1038/s41420-018-0117-7
  • Peer Reviewed / Open Access