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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.
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Nuclear actin is a critical regulator of Drosophila female germline stem cell maintenance
Nuclear actin has been implicated in regulating cell fate, differentiation, and cellular reprogramming. However, its roles in development and tissue homeostasis remain largely unknown. Here we uncover the role of nuclear actin in regulating stemness usingDrosophilaovarian germline stem cells (GSCs) as a model. We find that the localization and structure of nuclear actin is dynamic in the early germ cells. Nuclear actin recognized by anti-actin C4 is found in both the nucleoplasm and nucleolus of GSCs. The polymeric nucleoplasmic C4 pool is lost after the 2-cell stage, whereas the monomeric nucleolar pool persists to the 8-cell stage, suggesting that polymeric nuclear actin may contribute to stemness. To test this idea, we overexpressed nuclear targeted actin constructs to alter nuclear actin polymerization states in the GSCs and early germ cells. Increasing monomeric nuclear actin, but not polymerizable nuclear actin, causes GSC loss that ultimately results in germline loss. This GSC loss is rescued by simultaneous overexpression of monomeric and polymerizable nuclear actin. Together these data reveal that GSC maintenance requires polymeric nuclear actin. This polymeric nuclear actin likely plays numerous roles in the GSCs, as increasing monomeric nuclear actin disrupts nuclear architecture causing nucleolar hypertrophy, distortion of the nuclear lamina, and heterochromatin reorganization; all factors critical for GSC maintenance and function. These data provide the first evidence that nuclear actin, and in particular, its ability to polymerize, are critical for stem cell function and tissue homeostasisin vivo.
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- Award ID(s):
- 2017797
- PAR ID:
- 10537191
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- University of Iowa
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Posted Content:
- https://doi.org/10.1101/2024.08.27.609996
