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

• Published in: Cell reports (Cambridge) Vol. 11; no. 11; pp. 1809 - 1821
• Main Authors: Mao, Diane D., Gujar, Amit D., Mahlokozera, Tatenda, Chen, Ishita, Pan, Yanchun, Luo, Jingqin, Brost, Taylor, Thompson, Elizabeth A., Turski, Alice, Leuthardt, Eric C., Dunn, Gavin P., Chicoine, Michael R., Rich, Keith M., Dowling, Joshua L., Zipfel, Gregory J., Dacey, Ralph G., Achilefu, Samuel, Tran, David D., Yano, Hiroko, Kim, Albert H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.06.2015; Elsevier
• Subjects: Anaphase-Promoting Complex-Cyclosome - metabolism; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cdc20 Proteins - genetics; Cdc20 Proteins - metabolism; Cells, Cultured; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Mice; Neoplastic Stem Cells - metabolism; Neurons - metabolism; Signal Transduction; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.05.027

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. [Display omitted] •CDC20-APC drives the invasiveness and self-renewal of glioblastoma stem-like cells•CDC20 is essential for the in vivo tumorigenicity of glioblastoma stem-like cells•CDC20-APC operates through SOX2 to control glioblastoma stem-like cell function•CDC20 is prognostic of overall survival in Proneural subtype glioblastoma patients Mao et al. report that E3 ubiquitin ligase CDC20-APC is required for invasiveness, self-renewal, and in vivo tumorigenicity of human glioblastoma stem-like cells (GSCs). CDC20-APC interacts with and regulates SOX2 protein to promote SOX2-dependent transcription and drive GSC invasiveness and self-renewal. Using the Cancer Genome Atlas dataset, the authors find that high CDC20 expression in proneural glioblastomas is associated with shorter overall survival.