Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics
| Autor: | Christopher J. Bergin, Kinga Vojnits, Borko Tanasijevic, Zoya Shapovalova, Deanna P. Porras, Aïcha Zouggar, Meaghan Doyle, Luca Orlando, Angelique N. Masibag, Kalinka Koteva, Juan L. García-Rodríguez, Jagdish Suresh Patel, Jennifer Russell, Allison L. Boyd, Wenliang Wang, Ryan R. Mitchell, Tony J. Collins, Lili Aslostovar, Mickie Bhatia, Jakob Magolan, Gerard D. Wright, Yannick D. Benoit, Fanny L. Casado, Lakshmana K. Kinthada, Justin D. Lu, Sara N. Andres, Cody Caba |
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| Rok vydání: | 2021 |
| Předmět: |
Cell Survival
Clinical Biochemistry SUMO protein Antineoplastic Agents Genomics Ubiquitin-Activating Enzymes Biology Biochemistry Article Mice 03 medical and health sciences 0302 clinical medicine Neoplasms Cell Line Tumor Drug Discovery medicine Animals Humans Cell Self Renewal RNA Small Interfering Molecular Biology 030304 developmental biology Progenitor Pharmacology Biological Products 0303 health sciences Binding Sites Sumoylation medicine.disease Sumoylation Pathway Chemical space Cell biology Molecular Docking Simulation Leukemia Myeloid Acute Leukemia 030220 oncology & carcinogenesis Neoplastic Stem Cells Molecular Medicine RNA Interference Stem cell Protein Processing Post-Translational Function (biology) |
| Zdroj: | Cell Chem Biol |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2021.04.014 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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