Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Bioorg Med Chem. 2019 Jul 1;27(13):2998-3003. doi: 10.1016/j.bmc.2019.05.002. Epub 2019 May 4.
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 IC 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.
B 细胞特异性 Moloney 鼠白血病病毒区域 1（BMI1）是多梳抑制复合物 1（PRC1）的核心组成部分，通过染色质浓缩维持基因表达的表观遗传抑制。BMI1 的过表达下调肿瘤抑制基因的表达，如 p16Ink4a 和 PTEN。BMI1 在癌症干细胞（CSC）中表达上调。因此，BMI1 表达抑制剂具有作为癌症治疗剂的潜力。本研究旨在从放线菌中鉴定 BMI1 启动子抑制剂。使用最近构建的 BMI1 启动子测定法，我们从链霉菌 IFM-11958 中分离出三种已知化合物，即石蒜科素（1）、2-甲基石蒜科素（2）和诺卡米嗪（3），它们分别以 30 nM、447 nM 和 22 µM 的 IC 值抑制 BMI1 启动子活性。石蒜科素（1）的活性最强。Western blot 和 PCR 分析显示，石蒜科素（1）在人前列腺癌细胞（DU145）中抑制 BMI1 的 mRNA 水平表达。石蒜科素（1）还抑制人肝癌细胞（Huh7）的球体形成活性，表明石蒜科素（1）抑制 CSC 的自我更新能力。石蒜科素（1）是从放线菌代谢产物中分离出的第一个 BMI1 启动子抑制剂。
