1. Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics.
- Author
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Benoit, Yannick D., Mitchell, Ryan R., Wang, Wenliang, Orlando, Luca, Boyd, Allison L., Tanasijevic, Borko, Aslostovar, Lili, Shapovalova, Zoya, Doyle, Meaghan, Bergin, Christopher J., Vojnits, Kinga, Casado, Fanny L., Di Lu, Justin, Porras, Deanna P., García-Rodriguez, Juan Luis, Russell, Jennifer, Zouggar, Aïcha, Masibag, Angelique N., Caba, Cody, and Koteva, Kalinka
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CANCER stem cells , *HUMAN stem cells , *HUMAN biology , *STEM cells , *PROGENITOR cells - Abstract
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. [Display omitted] • Natural product compound (McM025044) has selective anti-neoplastic activity • McM025044 binds to SAE2 to reduce SUMOylation of intracellular proteins • SUMOylation inhibition by McM025044 impairs stem cell self-renewal • McM025044 restricts in vivo activity of SUMO-dependent leukemia initiating cells Benoit et al. screened extracts from strains of actinomycete to uncover and isolate a molecule that inhibits SUMOylation in human cancer stem cells. This natural product compound acts via biochemical targeting of a specific motif in a SUMOylation enzyme, SAE2, that regulates self-renewal of a variety of human cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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