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

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 Di Lu; Deanna P Porras; Juan Luis García-Rodriguez; Jennifer Russell; Aïcha Zouggar; Angelique N Masibag; Cody Caba; Kalinka Koteva; Lakshmana K Kinthada; Jagdish Suresh Patel; Sara N Andres; Jakob Magolan; Tony J Collins; Gerard D Wright; Mickie Bhatia

doi:10.1016/j.chembiol.2021.04.014

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. Epub 2021 May 11.

Authors

Yannick D Benoit¹, Ryan R Mitchell², Wenliang Wang³, Luca Orlando⁴, Allison L Boyd⁴, Borko Tanasijevic², Lili Aslostovar², Zoya Shapovalova², Meaghan Doyle⁴, Christopher J Bergin⁵, Kinga Vojnits⁴, Fanny L Casado², Justin Di Lu², Deanna P Porras⁴, Juan Luis García-Rodriguez⁴, Jennifer Russell², Aïcha Zouggar⁵, Angelique N Masibag⁵, Cody Caba⁶, Kalinka Koteva⁶, Lakshmana K Kinthada⁶, Jagdish Suresh Patel⁷, Sara N Andres⁶, Jakob Magolan⁸, Tony J Collins², Gerard D Wright⁹, Mickie Bhatia¹⁰

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Binding Sites
Biological Products / chemistry
Biological Products / metabolism
Biological Products / pharmacology
Biological Products / therapeutic use
Cell Line, Tumor
Cell Self Renewal
Cell Survival / drug effects
Humans
Leukemia, Myeloid, Acute / drug therapy
Leukemia, Myeloid, Acute / pathology
Mice
Molecular Docking Simulation
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Sumoylation / drug effects
Ubiquitin-Activating Enzymes / chemistry
Ubiquitin-Activating Enzymes / genetics
Ubiquitin-Activating Enzymes / metabolism*

Substances

Antineoplastic Agents
Biological Products
RNA, Small Interfering
UBA2 protein, human
Ubiquitin-Activating Enzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding