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
  • 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: [email protected].
  • 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: [email protected].
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.
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