Targeting EYA2 tyrosine phosphatase activity in glioblastoma stem cells induces mitotic catastrophe
Open Access
- 7 October 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 218 (11)
- https://doi.org/10.1084/jem.20202669
Abstract
Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.Funding Information
- National Institutes of Health (CA217066, CA217065, CA203101, CA184090, NS091080, NS099175, CA224867, CA221282, NS108396, CA197718, CA238662, NS103434)
- Danish Cancer Society
- KBVU Foundation
- Knæk Cancer
- NovoNordisk Foundation
- Singapore Ministry of Health
- National Medical Research Council (OFIRG17may050, NMRC/OFIRG/0051/2017)
This publication has 69 references indexed in Scilit:
- Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-β signaling, epithelial–mesenchymal transition, and cancer stem cell propertiesOncogene, 2011
- The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant GliomaCancer Cell, 2011
- Mechanisms of Centrosome Separation and Bipolar Spindle AssemblyDevelopmental Cell, 2010
- The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cellsOncogene, 2010
- Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes AbsentOnline Journal of Public Health Informatics, 2009
- Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trialThe Lancet Oncology, 2009
- Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisionsNature, 2009
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Extra centrosomes and/or chromosomes prolong mitosis in human cellsNature, 2008
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006