Title
Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics
Date Issued
21 October 2021
Access level
open access
Resource Type
journal article
Author(s)
Benoit Y.D.
Mitchell R.R.
Wang W.
Orlando L.
Boyd A.L.
Tanasijevic B.
Aslostovar L.
Shapovalova Z.
Doyle M.
Bergin C.J.
Vojnits K.
Di Lu J.
Porras D.P.
García-Rodriguez J.L.
Russell J.
Zouggar A.
Masibag A.N.
Caba C.
Koteva K.
Kinthada L.K.
Patel J.S.
Andres S.N.
Magolan J.
Collins T.J.
Wright G.D.
Bhatia M.
McMaster University
Publisher(s)
Elsevier Ltd
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.
Start page
1394
End page
1406.e10
Volume
28
Issue
10
Language
English
OCDE Knowledge area
Bioquímica, Biología molecular
Biología celular, Microbiología
Subjects
Scopus EID
2-s2.0-85117210820
PubMed ID
Source
Cell Chemical Biology
ISSN of the container
24519456
Sponsor(s)
This work was supported by grants from the Ontario Research Foundation (OCRiT) led by M.B. and the David Braley Foundation, work in this study related to human leukemia was funded and supported by CCS Impact Grant #706694, whereas results and studies using hPSCs was supported by Canadian Institutes of Health Research (CIHR) foundation grant FRN 159925 to M.B. approved by the Stem Cell Oversight Committee in Canada, and finally the Canada Research Chair in human stem cell biology (M.B.) CIHR for molecular studies of antibiotics (G.D.W.). Y.D.B. is supported by the NSERC (RGPIN-2018-06521), the Cancer Research Society (#24039), and the CIHR (PJT- 173541). J.S.P. was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number P20GM104420. Computer resources were provided by the Institute for Bioinformatics and Evolutionary Studies Computational Resources Core sponsored by the National Institutes of Health (P30 GM103324). We acknowledge the Center for Microbial Chemical Biology (CMCB) core facility and staff members Susan McCusker and Nikki Henriquez for assistance with protein production and mass spectrometry respectively. Y.D.B. and R.R.M designed and performed experiments, analyzed data, and wrote the paper. W.W. performed experiments and analyzed data. L.A. A.L.B. L.O. B.T. Z.S. M.D. J.L.G.-R. K.V. J.D.L. J.R. C.J.B. A.N.M. A.Z. and C.C. performed experiments. F.L.C. performed comet assay and preliminary mass spectrometry optimization of affinity pulldown. S.N.A. and J.M. designed and supervised experiments, and provided conceptual advice. T.J.C. designed and performed experiments, analyzed data, and wrote the paper. J.S.P designed, performed experiments, and provided conceptual advice. G.D.W. and M.B. designed experiments and supervised the project, provided final interpretation, and wrote the paper. The authors declare no competing financial interests. However, some authors are inventors of a provisional patent related to unique targeting of human cancer cells using SAE2 and related probe compounds.
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