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Cell Rep. 2015 Jun 23;11(11):1809-21. doi: 10.1016/j.celrep.2015.05.027. Epub 2015 Jun 11.

A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells.

Author information

1
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Division of Biostatistics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Program in Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
8
Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
9
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
10
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: kima@wudosis.wustl.edu.

Abstract

Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.

PMID:
26074073
PMCID:
PMC4481182
DOI:
10.1016/j.celrep.2015.05.027
[Indexed for MEDLINE]
Free PMC Article

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