Oncotarget

Research Papers:

CDC20 maintains tumor initiating cells

Qi Xie _, Qiulian Wu, Stephen C. Mack, Kailin Yang, Leo Kim, Christopher G. Hubert, William A. Flavahan, Chengwei Chu, Shideng Bao and Jeremy N. Rich

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Oncotarget. 2015; 6:13241-13254. https://doi.org/10.18632/oncotarget.3676

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Abstract

Qi Xie1, Qiulian Wu1, Stephen C. Mack1, Kailin Yang1,2, Leo Kim1, Christopher G. Hubert1, William A. Flavahan1,3,4,5, Chengwei Chu1,6, Shideng Bao1,2, Jeremy N. Rich1,2

1Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA

2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA

3Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

4Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA

5Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA

6Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan

Correspondence to:

Jeremy N. Rich, e-mail: drjeremyrich@gmail.com

Keywords: cancer stem cell, glioblastoma, glioma, tumor initiating cell, CDC20

Received: March 05, 2015     Accepted: April 16, 2015     Published: April 28, 2015

ABSTRACT

Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes – FOXM1 and p21CIP1/WAF1 — elucidating a potential point for therapeutic intervention.


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