Targeting EYA2 tyrosine phosphatase activity in glioblastoma stem cells induces mitotic catastrophe
Year: 2021
Type: article
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.
DOI: 10.1084/jem.20202669
Authors: Guoxin Zhang, Zhen Dong, Ryan C. Gimple, Arthur Wolin, Qiulian Wu, Zhixin Qiu, Lisa M. Wood, Jia Z. Shen, Li Jiang, Linjie Zhao, Deguan Lv, Briana C. Prager, Leo J.Y. Kim, Xiuxing Wang, Lingdi Zhang, Ryan L. Anderson, Jeffrey K. Moore, Shideng Bao, Thomas H. Keller, Grace Lin, Congbao Kang, Petra Hamerlik, Rui Zhao, Heide L. Ford, Jeremy N. Rich
Institutions: University of California San Diego, Case Western Reserve University, University of Colorado Anschutz, University of Colorado Denver, Sanford Burnham Prebys Medical Discovery Institute, National Cancer Institute, Cleveland Clinic, Agency for Science, Technology and Research, Experimental Drug Development Centre, University of Copenhagen, Danish Cancer Society, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Kræftens Bekæmpelse, Ministry of Health -Singapore, Novo Nordisk Foundation Center for Basic Metabolic Research, National Institutes of Health, National Medical Research Council, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2 (R01NS103434), G1224449398, G1436032867, G1665110821, G2264348815, G2315391593, G2801183991, Targeting TCA cycle in Brain Tumor Initiating Cells, Examining the EYA2/MYC axis in Group 3 Medulloblastoma, G4516348428, G5228119296, Glioblastoma stem cell-derived pericytes and cancer invasion, Dynamic Complexity of Brain Tumor Stem Cells (R35CA197718), G7371629149, G8830816033, G9000018383, G9000127388, G9000211328, G9000236610, G9000240694, G9000255107, G9000292995, University of Colorado Cancer Center Support Grant
OpenAlex ID: W3203230346