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Basic research for elucidation of growth mechanism of testicular tumor by LSD1 and development of therapeutic method by its inhibitor

Research Project

Project/Area Number 17K11152
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Urology
Research InstitutionNagoya City University

Principal Investigator

Akita Hidetoshi  名古屋市立大学, 医薬学総合研究院(医学), 研究員 (10381782)

Co-Investigator(Kenkyū-buntansha) 安井 孝周  名古屋市立大学, 医薬学総合研究院(医学), 教授 (40326153)
河合 憲康  名古屋市立大学, 医薬学総合研究院(医学), 准教授 (20254279)
安藤 亮介  名古屋市立大学, 医薬学総合研究院(医学), 教授 (30381867)
内木 拓  名古屋市立大学, 医薬学総合研究院(医学), 講師 (50551272)
飯田 啓太郎  名古屋市立大学, 医薬学総合研究院(医学), 臨床研究医 (30713945)
惠谷 俊紀  名古屋市立大学, 医薬学総合研究院(医学), 助教 (30600754)
内木 綾  名古屋市立大学, 医薬学総合研究院(医学), 准教授 (20509236)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
KeywordsLSD1 / エピゲノム / メチル化 / 阻害剤 / 精巣腫瘍 / アポトーシス / 同所移植モデル / 臨床検体 / 血管新生阻害 / 腫瘍マーカー / 癌 / 細胞・組織 / マイクロアレイ / オートファジー
Outline of Final Research Achievements

LSD1, the first histone demethylase to be discovered, is a novel target in prostate cancer therapy. NCL1 and NCD38, novel selective cell-active inhibitors of LSD1, were discovered at our university. We analyzed the efficacy of LSD1 inhibitors in germ cell tumors.
The WST assay revealed a reduction in the number of viable cells in a dose-dependent manner after NCL1 or NCD38 treatment. In western blotting, NCL1 or NCD38 treatment induced caspase-dependent apoptosis, while Oct4 and SOX2 expression was decreased. In flow cytometry analysis, NCL1 or NCD38 significantly induced apoptosis in a dose-dependent manner. Subcutaneous tumor volumes and serum AFP levels were significantly lower in mice treated with NCL1 or NCD38 than in controls. TUNEL analysis showed that NCL1 and NCD38 treatment induced apoptosis in NTERA2 subcutaneous tumors. Tissue array analysis showed that LSD1 expression in human seminoma specimens was significantly higher than that in noncancerous specimens.

Academic Significance and Societal Importance of the Research Achievements

精巣腫瘍は化学療法で根治が期待できる腫瘍である。しかし、初回治療に抵抗性となると有効な治療法が少ない。さらに、悪性度の高い非セミノーマは若年者に多く、新規治療法の確立が求められている。ヒストン脱メチル化酵素LSD1は精巣腫瘍におけるエピジェネティックな増殖メカニズムで重要であり、治療標的として注目されている。今回私たちは、LSD1の新規阻害剤であるNCL1およびNCD38は精巣腫瘍において、新規治療薬となる可能性を示唆する基礎的な研究結果を得た。本研究は、精巣腫瘍に対してこれまでの治療法とは全く異なるエピゲノム治療の可能性を示した点で、学術的および社会的に意義深いと考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (5 results)

All 2020 2019 2018 2017

All Presentation (5 results) (of which Int'l Joint Research: 2 results)

  • [Presentation] Novel selective lysine-specific demethylase 1 inhibitors suppress testicular tumor cell proliferation2020

    • Author(s)
      Etani Toshiki, Naiki Taku, Nozaki Satoshi, Nagai Takashi, Iida Keitaro, Ando Ryosuke, Kawai Noriyau, Takahashi Satoru, Suzuki Takayoshi, Yasui Takahiro
    • Organizer
      American Urological Association Annual Meeting 2020
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 精巣悪性腫瘍に対するヒストン脱メチル化酵素LSD1阻害剤の治療効果に関する基礎的研究2019

    • Author(s)
      惠谷 俊紀、内木 拓、永井 隆、飯田 啓太郎、安藤 亮介、河合 憲康、戸澤 啓一、鈴木 孝禎、安井 孝周
    • Organizer
      第107回日本泌尿器科学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] A selective lysine-specific demethylase 1 inhibitor suppresses testicular tumor proliferation2019

    • Author(s)
      Etani Toshiki, Naiki Taku, Nozaki Satoshi, Nagai Takashi, Iida Keitaro, Ando Ryosuke, Kawai Noriyasu, Takahashi Satoru, Suzuki Takayoshi, Yasui Takahiro
    • Organizer
      American Urological Association Annual Meeting 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 精巣悪性腫瘍に対するヒストン脱メチル化酵素阻害剤の治療効果2018

    • Author(s)
      惠谷 俊紀、内木 拓、永井 隆、田中 勇太朗、飯田 啓太郎、安藤 亮介、河合 憲康、戸澤 啓一、鈴木 孝禎、安井 孝周
    • Organizer
      第106回日本泌尿器科学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] A selective lysine-specific demethylase1 inhibitor suppresses germ cell tumor proliferation.2017

    • Author(s)
      Etani Toshiki, Naiki Taku, Nagai Takashi, Iida Keitaro, Ando Ryosuke, Kawai Noriyasu, Takahashi Satoru, Suzuki Takayoshi, Yasui Takahiro
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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