Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada.
Cell Chem Biol. 2021 Oct 21;28(10):1394-1406.e10. doi: 10.1016/j.chembiol.2021.04.014. Epub 2021 May 11.
Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.
天然产物（NPs）包含丰富的生物活性化学实体来源。在这里，我们在一个化学基因组学活动中使用人类癌症干细胞（CSCs），用 NP 化学空间来研究来自不同放线菌菌株的提取物的抗癌特性。我们发现了一种化合物（McM25044），能够选择性地抑制人类 CSC 功能，而对正常干细胞没有影响。生化和分子研究表明，McM025044 通过小泛素样修饰物（SUMO）级联反应抑制人类 CSCs，该级联反应在多种人类癌症中过度活跃。McM025044 通过直接靶向 SAE1/2 复合物来抑制 SUMO 化途径。对患者来源的 CSCs 的治疗导致 SUMO 化蛋白水平降低，并抑制了体外和体内测量的祖细胞和干细胞能力。我们的研究克服了化学抑制致癌 SUMO 化活性的障碍，并揭示了 SAE2 在人类癌症生物学中的独特作用。
