Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics.

Autor:	Benoit YD; 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., Mitchell RR; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Wang W; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada., Orlando L; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Boyd AL; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Tanasijevic B; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Aslostovar L; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Shapovalova Z; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Doyle M; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Bergin CJ; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada., Vojnits K; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Casado FL; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Di Lu J; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Porras DP; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., García-Rodriguez JL; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Russell J; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Zouggar A; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada., Masibag AN; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada., Caba C; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Koteva K; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Kinthada LK; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Patel JS; Department of Biological Sciences, Institute for Modeling Collaboration and Innovation, University of Idaho, Moscow, ID 83844, USA., Andres SN; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Magolan J; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada., Collins TJ; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada., Wright GD; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address: wrightge@mcmaster.ca., Bhatia M; Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address: mbhatia@mcmaster.ca.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2021 Oct 21; Vol. 28 (10), pp. 1394-1406.e10. Date of Electronic Publication: 2021 May 11.
DOI:	10.1016/j.chembiol.2021.04.014
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing financial interests. However, some authors are inventors of a provisional patent related to unique targeting of human cancer cells using SAE2 and related probe compounds. (Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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