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

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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.

authors

  • 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
  • Magolan, Jakob
  • Collins, Tony J
  • Wright, Gerard
  • Bhatia, Mick

publication date

  • October 2021