NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells.

Yang Jiang,Run Wang,Di Zhang,Xinxin Tie,Yifu Song,Tianhao Hu,Minghao Wang,Sheng Han,Zixun Wang

doi:10.1158/0008-5472.can-18-3297

Abstract

Glioma stem-like cells (GSC) promote tumor generation and progression. However, the mechanism of GSC induction or maintenance is largely unknown. We previously demonstrated that the calcium-responsive transcription factor nuclear factor of activated T cells-1 (NFAT1) is activated in glioblastomas and regulates the invasion of tumor cells. In this study, we further explored the role of NFAT1 in GSC. We found that NFAT1 expression was associated with an aggressive phenotype and predicted poor survival in gliomas. Compared with normal glioma cells, NFAT1 was upregulated in GSC. NFAT1 knockdown reduced GSC viability, invasion, and self-renewal in vitro and inhibited tumorigenesis in vivo, whereas NFAT1 overexpression enhanced the growth and invasion of GSCs. RNA sequencing showed that NFAT1 depletion was associated with reduced neurodevelopment protein 1-like 1 (NDEL1, a potential downstream target of NFAT1) expression, whereas NFAT1 overexpression induced NDEL1 expression. In addition, NFAT1 regulated the promoter activities of NDEL1, whereas rescue of NDEL1 in NFAT1-silenced GSC partially restored tumor growth and invasion. Upregulation of NFAT1-NDEL1 signaling elevated Erk activation, increased protein levels of stemness markers in GSC, and resulted in de-differentiation of normal neuronal cells and astrocytes. Our results indicate that NFAT1 controls the growth and invasion of GSC partially through regulation of NDEL1. Targeting the NFAT1-NDEL1 axis therefore might be of potential benefit in the treatment of patients with glioma. SIGNIFICANCE: NFAT1 controls the growth and invasion of GSCs, partially by regulating NDEL1. Targeting the NFAT1-NDEL1 axis might provide opportunities in treating patients with glioma.

Highlights

Glioma is the most common and therapeutically intractable primary brain tumor in adults [1]
We found that the levels of nuclear factor of activated T cells-1 (NFAT1) expression were higher in the mesenchymal subtype compared with the classical, neural, and proneural subtypes according to The Cancer Genome Atlas (TCGA) (Fig. 1A) and Gravendeel datasets (Supplementary Fig. S1A)
Results are presented as the mean Æ SEM of triplicate samples from three independent experiments

Summary

Introduction

Glioma is the most common and therapeutically intractable primary brain tumor in adults [1]. Gliomas contain a subpopulation of cells exhibiting stem cell-like properties, including selfrenewal activity, multi-lineage differentiation potential, and stem cell marker expression, which are called glioma stem cells or glioma stem-like cells (GSC). GSCs may play a central role in tumor initiation, therapy resistance, and recurrence. Efficacious glioma treatments need to target this subpopulation of cells [2]. Revealing the biological and molecular mechanisms driving GSCs self-renewal and migration is important for the development of GSC directed therapies as GSCs are located in special microenvironments [3]. Accumulating evidence indicates that inflammatory factors, calcium signaling, and hypoxia within the microenvironment regulate the stemness, survival, and inva-

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Results

Conclusion