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Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon
Anqi Xiong1,2, Ananya Roy1, Argyris Spyrou1,3
1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Abstract:
Pseudokinases, comprising 10% of the human kinome, are emerging as regulators of canonical kinases and their functions are starting to be defined. We previously identified the pseudokinase Nuclear Receptor Binding Protein 2 (NRBP2) in a screen for genes regulated during neural differentiation. During mouse brain development, NRBP2 is expressed in the cerebellum, and in the adult brain, mainly confined to specific neuronal populations. To study the role of NRBP2 in brain tumors, we stained a brain tumor tissue array for NRPB2, and find its expression to be low, or absent, in a majority of the tumors. This includes medulloblastoma (MB), a pediatric tumor of the cerebellum. Using database mining of published MB data sets, we also find that NRBP2 is expressed at a lower level in MB than in the normal cerebellum. Recent studies indicate that MB exhibits frequent epigenetic alternations and we therefore treated MB cell lines with drugs inhibiting DNA methylation or histone deacetylation, which leads to an upregulation of NRBP2 mRNA expression, showing that it is under epigenetic regulation in cultured MB cells. Furthermore, forced overexpression of NRBP2 in MB cell lines causes a dramatic decrease in cell numbers, increased cell death, impaired cell migration and inhibited cell invasion in vitro. Taken together, our data indicate that downregulation of NRBP2 may be a feature by which MB cells escape growth regulation.
Insights
Nuclear Receptor Binding Protein 2 (NRBP2) is downregulated in medulloblastoma, a pediatric brain tumor. Restoring NRBP2 expression inhibits tumor cell growth, suggesting NRBP2 acts as a tumor suppressor.
Area of Science:
- Biochemistry
- Neuroscience
- Oncology
Background:
- Pseudokinases are emerging regulators of canonical kinases.
- Nuclear Receptor Binding Protein 2 (NRBP2) is a pseudokinase identified during neural differentiation.
- NRBP2 expression is observed in the developing and adult brain, particularly the cerebellum.
Purpose of the Study:
- To investigate the role of NRBP2 in brain tumors, specifically medulloblastoma (MB).
- To determine the expression levels and regulation of NRBP2 in MB.
- To assess the functional impact of NRBP2 on MB cell behavior.
Main Methods:
- Brain tumor tissue array staining for NRBP2 expression.
- Bioinformatic analysis of NRBP2 expression in MB datasets.
- Treatment of MB cell lines with epigenetic modifying drugs (DNA methylation inhibitors, histone deacetylase inhibitors).
- Forced overexpression of NRBP2 in MB cell lines followed by in vitro assays.
Main Results:
- NRBP2 expression is low or absent in a majority of brain tumors, including MB.
- NRBP2 is downregulated in MB compared to normal cerebellum tissue.
- Epigenetic modulation (DNA methylation inhibition, histone deacetylation inhibition) upregulates NRBP2 mRNA in MB cell lines.
- Overexpression of NRBP2 in MB cells leads to decreased cell proliferation, increased cell death, and reduced migration and invasion.
Conclusions:
- Downregulation of NRBP2 is a potential mechanism for medulloblastoma cells to evade growth control.
- NRBP2 functions as a tumor suppressor in medulloblastoma.
- NRBP2 represents a potential therapeutic target for medulloblastoma.
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