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

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

  • Cell Chem Biol. 2021 Oct 21;28(10):1394-1406.e10. doi: 10.1016/j.chembiol.2021.04.014.
Yannick D Benoit 1,  Ryan R Mitchell 2,  Wenliang Wang 3,  Luca Orlando 4,  Allison L Boyd 4,  Borko Tanasijevic 2,  Lili Aslostovar 2,  Zoya Shapovalova 2,  Meaghan Doyle 4,  Christopher J Bergin 5,  Kinga Vojnits 4,  Fanny L Casado 2,  Justin Di Lu 2,  Deanna P Porras 4,  Juan Luis García-Rodriguez 4,  Jennifer Russell 2,  Aïcha Zouggar 5,  Angelique N Masibag 5,  Cody Caba 6,  Kalinka Koteva 6,  Lakshmana K Kinthada 6,  Jagdish Suresh Patel 7,  Sara N Andres 6,  Jakob Magolan 8,  Tony J Collins 2,  Gerard D Wright 9,  Mickie Bhatia 10
Affiliations

Affiliations

  • 1 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.
  • 2 Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada.
  • 3 M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton L8S 4K1, Canada.
  • 4 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
  • 5 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
  • 6 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.
  • 7 Department of Biological Sciences, Institute for Modeling Collaboration and Innovation, University of Idaho, Moscow, ID 83844, USA.
  • 8 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.
  • 9 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.
  • 10 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.
PMID: 33979648 DOI: 10.1016/j.chembiol.2021.04.014
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.

Keywords

SUMOylation; drug; leukemia; natural products; screening; selectivity; stem cells.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108702
    99.90%, SUMO-Activating Enzyme Inhibitor