Journal article
CDC20 maintains tumor initiating cells
Oncotarget, Vol.6(15), pp.13241-13254
05/30/2015
DOI: 10.18632/oncotarget.3676
PMCID: PMC4537011
PMID: 25938542
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 p21(CIP1/WAF1), a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21(CIP1/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 p21(CIP1/WAF1) - elucidating a potential point for therapeutic intervention.
Details
- Title: Subtitle
- CDC20 maintains tumor initiating cells
- Creators
- Qi Xie - Cleveland Clinic Lerner College of MedicineQiulian Wu - Cleveland Clinic Lerner College of MedicineStephen C. Mack - Cleveland Clinic Lerner College of MedicineKailin Yang - Cleveland Clinic Lerner College of MedicineLeo Kim - Cleveland Clinic Lerner College of MedicineChristopher G. Hubert - Cleveland Clinic Lerner College of MedicineWilliam A. Flavahan - Cleveland Clinic Lerner College of MedicineChengwei Chu - Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USAShideng Bao - Cleveland Clinic Lerner College of MedicineJeremy N. Rich - Cleveland Clinic Lerner College of Medicine
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.6(15), pp.13241-13254
- DOI
- 10.18632/oncotarget.3676
- PMID
- 25938542
- PMCID
- PMC4537011
- NLM abbreviation
- Oncotarget
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals Llc
- Number of pages
- 14
- Grant note
- James S. McDonnell Foundation R01CA171652 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01NS087913 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Research Programs Committees of Cleveland Clinic CA154130; CA171652; CA169117; NS087913; NS089272; CA155764; NS070315 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32GM007250 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 05/30/2015
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696582602771
Metrics
15 Record Views