A Tumor Suppressor Gene, N-myc Downstream-Regulated Gene 1 (NDRG1), in Gliomas and Glioblastomas

Abstract

The development of potent and selective therapeutic approaches to glioblastoma (GBM) requires the identification of molecular pathways that critically regulate the survival and proliferation of GBM. Glioblastoma stem-like cells (GSCs) possess stem-cell-like properties, self-renewal, and differentiation into multiple neural cell lineages. From a clinical point of view, GSCs have been reported to resist radiation and chemotherapy. GSCs are influenced by the microenvironment, especially the hypoxic condition. N-myc downstream-regulated gene 1 (NDRG1) is a tumor suppressor with the potential to suppress the proliferation, invasion, and migration of cancer cells. Previous studies have reported that deregulated expression of NDRG1 affects tumor growth and clinical outcomes of patients with GBM. This literature review aimed to clarify the critical role of NDRG1 in tumorigenesis and acquirement of resistance for anti-GBM therapies, further to discussing the possibility and efficacy of NDRG1 as a novel target of treatment for GBM. The present review was conducted by searching the PubMed and Scopus databases. The search was conducted in February 2022. We review current knowledge on the regulation and signaling of NDRG1 in neuro-oncology. Finally, the role of NDRG1 in GBM and potential clinical applications are discussed.

Keywords: N-myc downstream-regulated gene 1; glioblastoma; glioblastoma stem-like cells.

Figure 1

Phenotypic and molecular characteristics of the three layers that comprise the glioblastoma tumor.

Figure 2

Schematic diagram of the putative functions of NDRG1 in normal or cancer cells. The NDRG1 protein responds to stress and induces genome stability, differentiation, myelination, maintenance of T cell clonal anergy, lipid synthesis, and vesicle transport. In cancer cells, NDRG1 has an inhibitory action on cell proliferation, invasion, migration, metastasis, and angiogenesis, and promotes apoptosis and differentiation. Abbreviations: AP1, activator protein 1; VEGF, vascular endothelial growth factor; IL-8, interleukin-8.

Figure 3

Simplified schematic showing the interaction of NDRG1 with EMT-related genes in references [32,41]. Elevated protein expression of NDRG1 in the cytoplasm is stimulatory to E-cadherin, whereas vimentin and N-cadherin are repressively regulated through the PTEN/AKT pathway in both references. MORC2, which is an oncogene that binds with histone deacetylase 4 and acts as a transcriptional repressor, is studied in reference [41]. Abbreviations: MORC2, microrchidia family CW-type zinc finger 2.

Figure 4

A simplified diagram of the sites associated with NDRG1 of agents reported as candidates for GBM treatment and changes in NDRG1 expression.