Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon Overexpression

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.

MethylSPWNet and MethylCapsNet: Biologically Motivated Organization of DNAm Neural Network, Inspired by Capsule Networks

“…We also found associations with the Opioid-signaling pathway and G alpha (i) signaling events [67], and the tyrosine kinase receptor pathway VEGFR (Vascular Endothelial Growth Factor Receptor) and downstream signaling pathway ERK (Figure 3C-D), largely involved with proliferation and angiogenesis [68]. Regarding MB, as examples, we uncovered NRBP2 (Nuclear Receptor Binding Protein 2; Figure 3F), which had been shown to be downregulated in MB[69], and SOX14 (Figure 3F), part of the SOX family which largely determines cell fate and thus heavily implicated across many CNS tumors[70]. Additionally, pathways such as Muscle Contraction (Figure 3E-F) have been associated with specific molecular subtypes of MB [14,71].…”

NRBP2 Functions as a Tumor Suppressor and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer

“…In addition, NRBP2 is expressed in the hippocampus and ventricular wall of the embryonic mouse brain, whereas it is mainly located in hippocampal neurons and Purkinje cells in the adult brain ( 9 ). Based on emerging evidence, NRBP2 participates in the progression of various tumors by inhibiting the proliferation and metastasis of tumor cells and promoting tumor cell apoptosis ( 10 , 11 ). As shown in the present study, NRBP2 overexpression markedly increased cell proliferation and invasion in vitro , and promoted the lung metastasis of BC cells in vivo .…”

“…During tumor progression, NRBP2 is consistently regarded as a tumor suppressor gene (13). NRBP2 causes the death of NSPCs, medulloblastoma cells and HCC cells (9)(10)(11). It also positively regulates the cytotoxic effects of chemotherapy in HCC (11).…”

“…Nuclear Receptor Binding Protein 2 (NRBP2) is a 55–60 kDa conserved protein ( 9 ) with a cytoplasmic localization in neural stem/progenitor cells (NSPCs) ( 9 ), brain tumor cells ( 10 ) and HCC cells ( 11 ). The NRBP family is initially involved in the transport between the endoplasmic reticulum and Golgi ( 12 ).…”

The role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors

“…A recent study has indicated that MB shows frequent epigenetic alternations, so Anqi Xiong et al [ 67 ] treated MB cell lines with drugs that inhibited DNA methylation or histone deacetylation and found in their study that NRBP2 mRNA expression was up-regulated, indicating that it is under epigenetic regulation in cultured MB cells. In addition, forced overexpression of NRBP2 in MB cell lines results in a dramatic reduction in cell number, increased cell death, impaired cell migration and inhibition of cell invasion in vitro.…”