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

2021; Elsevier BV; Volume: 28; Issue: 10 Linguagem: Inglês

10.1016/j.chembiol.2021.04.014

2451-9456

Yannick D. Benoit, Ryan R. Mitchell, Wenliang Wang, Luca Orlando, Allison L. Boyd, Borko Tanasijevic, Lili Aslostovar, Zoya Shapovalova, Meaghan Doyle, Christopher J. Bergin, Kinga Vojnits, Fanny L. Casado, Justin D. Lu, Deanna P. Porras, Juan L. García-Rodríguez, Jennifer Russell, Aïcha Zouggar, Angelique N. Masibag, Cody Caba, Kalinka Koteva, Lakshmana K. Kinthada, Jagdish Suresh Patel, Sara N. Andres, Jakob Magolan, Tony Collins, Gerard D. Wright, Mickie Bhatia,

Click Chemistry and Applications

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.