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Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics.
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; Koteva, Kalinka; Kinthada, Lakshmana K; Patel, Jagdish Suresh; Andres, Sara N; Magolan, Jakob; Collins, Tony J; Wright, Gerard D; Bhatia, Mickie.
Afiliação
  • 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, Cana
  • 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, Cana
  • 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.
Cell Chem Biol ; 28(10): 1394-1406.e10, 2021 10 21.
Article em En | MEDLINE | ID: mdl-33979648
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Enzimas Ativadoras de Ubiquitina Limite: Animals / Humans Idioma: En Revista: Cell Chem Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Enzimas Ativadoras de Ubiquitina Limite: Animals / Humans Idioma: En Revista: Cell Chem Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá