CDC20 maintains tumor initiating cells.

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.

• Authors: Qi Xie, Qiulian Wu, Stephen C Mack, Kailin Yang, Leo Kim, Christopher G Hubert, William A Flavahan, Chengwei Chu, Shideng Bao, Jeremy N Rich
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 15 Pg. 13241-54 (May 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25938542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cdc20 Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• FOXM1 protein, human
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• CDC20 protein, human

Topics

• Animals
• Blotting, Western
• Brain Neoplasms (metabolism, pathology)
• Cdc20 Proteins (metabolism)
• Cell Proliferation (physiology)
• Cell Survival (physiology)
• Chromatin Immunoprecipitation
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Forkhead Box Protein M1
• Forkhead Transcription Factors (metabolism)
• Glioblastoma (metabolism, pathology)
• Heterografts
• Humans
• Mice
• Mice, Inbred NOD
• Neoplastic Stem Cells (metabolism)
• Tumor Cells, Cultured