Sam68 Allows Selective Targeting of Human Cancer Stem Cells

Yannick D Benoit; Ryan R Mitchell; Ruth M Risueño; Luca Orlando; Borko Tanasijevic; Allison L Boyd; Lili Aslostovar; Kyle R Salci; Zoya Shapovalova; Jennifer Russell; Masakatsu Eguchi; Diana Golubeva; Monica Graham; Anargyros Xenocostas; Michael R Trus; Ronan Foley; Brian Leber; Tony J Collins; Mickie Bhatia

doi:10.1016/j.chembiol.2017.05.026

Sam68 Allows Selective Targeting of Human Cancer Stem Cells

Cell Chem Biol. 2017 Jul 20;24(7):833-844.e9. doi: 10.1016/j.chembiol.2017.05.026. Epub 2017 Jun 22.

Authors

Yannick D Benoit¹, Ryan R Mitchell¹, Ruth M Risueño¹, Luca Orlando¹, Borko Tanasijevic¹, Allison L Boyd¹, Lili Aslostovar², Kyle R Salci³, Zoya Shapovalova¹, Jennifer Russell¹, Masakatsu Eguchi⁴, Diana Golubeva³, Monica Graham¹, Anargyros Xenocostas⁵, Michael R Trus⁶, Ronan Foley⁶, Brian Leber⁶, Tony J Collins¹, Mickie Bhatia⁷

Affiliations

¹ McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4L8, Canada.
² McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.
³ Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.
⁴ Theriac Pharmaceutical Corporation Research Institute, 600 Broadway Suite 580 Fl 5, Seattle, WA 98122, USA.
⁵ Department of Medicine, Division of Hematology, Schulich School of Medicine, University of Western Ontario, London, ON N6A 3K7, Canada.
⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁷ McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. Electronic address: mbhatia@mcmaster.ca.

PMID: 28648376
DOI: 10.1016/j.chembiol.2017.05.026

Abstract

Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs. Disruption of CBP-β-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction. Our study identifies Sam68 as a regulator of human CSC vulnerability.

Keywords: CBP; SUMOylation; Sam68; Wnt/β-catenin; cancer stem cells; differentiation; drug; leukemia; selectivity.

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Adult
Aged
Animals
Apoptosis / drug effects
Azabicyclo Compounds / pharmacology
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Differentiation / drug effects
Cells, Cultured
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Female
Humans
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Male
Mice
Mice, Inbred NOD
Middle Aged
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / transplantation
Organophosphates / pharmacology
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / genetics
Peptide Fragments / metabolism*
Proto-Oncogene Proteins c-myc / metabolism
Pyrimidinones / pharmacology
RNA Interference
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Sialoglycoproteins / antagonists & inhibitors
Sialoglycoproteins / genetics
Sialoglycoproteins / metabolism*
Sumoylation / drug effects
Transcriptome / drug effects
Wnt Signaling Pathway / drug effects
beta Catenin / metabolism

Substances

Adaptor Proteins, Signal Transducing
Azabicyclo Compounds
Bridged Bicyclo Compounds, Heterocyclic
CWP232228
DNA-Binding Proteins
ICG 001
KHDRBS1 protein, human
Organophosphates
Peptide Fragments
Proto-Oncogene Proteins c-myc
Pyrimidinones
RNA-Binding Proteins
Sialoglycoproteins
beta Catenin
bone sialoprotein (35-62), human