Identification of BMI1 promoter inhibitors from Streptomyces sp. IFM-11958

Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi

研究成果: Article査読

7 被引用数 (Scopus)

抄録

B-cell-specific Moloney murine leukemia virus region 1 (BMI1) is a central component of polycomb repressive complex 1 (PRC1), which maintains epigenetic repression of genes expression via chromatin condensation. BMI1 overexpression downregulates the expression of tumor suppressor genes, such as p16Ink4a and PTEN. BMI1 expression is upregulated in cancer stem cells (CSCs). Therefore, inhibitors of BMI1 expression have potential as therapeutic agents for cancer. This study aimed to identify BMI1 promoter inhibitors from actinomycetes. Using a recently constructed BMI1 promoter assay, we isolated three known compounds, elaiophylin (1), 2-methylelaiophylin (2), and nocardamin (3), from Streptomyces sp. IFM-11958 that inhibited BMI1 promoter activity with IC50 values of 30 nM, 447 nM, 22 µM, respectively. Elaiophylin (1) was the most potent. Western blot and PCR analyses revealed that elaiophylin (1) inhibited BMI1 expression at the mRNA level in human prostate cancer cells (DU145). Elaiophylin (1) also inhibited the sphere-forming activity of human hepatocellular carcinoma cells (Huh7), indicating that elaiophylin (1) suppresses the self-renewal capacity of CSCs. Elaiophylin (1) is the first BMI1 promoter inhibitor isolated from actinomycete metabolites.

本文言語English
ページ(範囲)2998-3003
ページ数6
ジャーナルBioorganic and Medicinal Chemistry
27
13
DOI
出版ステータスPublished - 2019 7月 1
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学

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