NDRG2

NDRG2 Full Name

N-myc downstream regulated gene 2

NDRG2 Introduction

NDRG2 (NDRG family member 2) is a cytoplasmic protein that belongs to the N-myc downstream-regulated gene family, so named because the founding members were identified as targets repressed by the N-myc oncoprotein. Although NDRG2 lacks enzymatic domains, it acts as a differentiation-associated protein whose abundance rises as cells mature and whose loss is repeatedly observed in aggressive cancers. Originally cloned from normal brain and glial cells, NDRG2 is strongly expressed in tissues such as the brain, skeletal muscle, kidney, and testis, and its expression is induced by diverse stimuli including steroid hormones, cellular stress, and agents that promote differentiation. In glioblastoma, the most common and deadly primary brain tumor, NDRG2 expression is markedly reduced or absent, and experimental restoration of the protein suppresses tumor cell proliferation, migration, and invasion while sensitizing cells to chemotherapy. Similar tumor-suppressive behavior has been described in hepatocellular carcinoma, colorectal cancer, and other malignancies, where promoter methylation frequently silences the gene. NDRG2 also contributes to normal physiology beyond cancer, including the regulation of aldosterone-responsive sodium transport in the kidney and the modulation of insulin sensitivity in metabolic tissues, making it a molecule of broad biological and clinical interest.

Figure 1. NDRG2 contributes to cisplatin sensitivity.(Park S, 2018)

Protein Features, Regulation of Expression, and Signaling Context
The NDRG2 protein shares the alpha/beta hydrolase fold characteristic of the NDRG family, yet it lacks the catalytic residues needed for enzymatic activity and is therefore believed to function primarily through protein-protein interactions.
The NDRG2 gene is located on human chromosome 14, and its promoter contains binding sites for transcription factors that respond to hormones, hypoxia, and differentiation signals.
Expression of NDRG2 is tightly controlled: it is silenced or downregulated in many tumors through promoter hypermethylation, whereas differentiating or stress conditions strongly induce the transcript.
Within the cell, NDRG2 is predominantly cytoplasmic but can shuttle to the nucleus, and its localization and stability are influenced by phosphorylation.
The protein interacts with signaling effectors that regulate cell survival and cytoskeletal dynamics, and it has been placed upstream of pathways such as PI3K/Akt and MAPK signaling in various experimental systems.
Because its expression so closely tracks the differentiated state of a cell, NDRG2 is widely used as a marker of differentiation in studies of glial, muscle, and epithelial cells.
The diversity of NDRG2-inducing stimuli points to a role as an integrator that converts extracellular cues into changes in cell growth and differentiation.

Differentiation, Tumor Suppression in Glioblastoma and Beyond, and Renal Physiology
In the nervous system NDRG2 is expressed by mature astrocytes and oligodendrocyte-lineage cells, and its induction accompanies the differentiation of neural progenitors, linking the protein to the acquisition of the mature glial phenotype.
Glioblastoma cells typically show loss of NDRG2, and restoring its expression inhibits proliferation and invasion, induces apoptosis, and improves the response of tumor cells to temozolomide and radiation in preclinical models.
Patients whose glioblastomas retain higher NDRG2 expression tend to have a somewhat better prognosis, supporting the idea that NDRG2 restrains tumor aggressiveness.
In the kidney, NDRG2 is regulated by aldosterone and modulates the activity of ion transport proteins, contributing to sodium homeostasis and blood pressure control.
In metabolic tissues NDRG2 influences insulin signaling, and altered NDRG2 levels have been connected to glucose metabolism and to the complications of diabetes.
The broad pattern of NDRG2 loss in epithelial cancers, frequently through epigenetic silencing, has motivated the evaluation of NDRG2 methylation as a biomarker and of demethylating strategies to restore its tumor-suppressive activity.

Alternate Names for NDRG2

NDRG2; N-myc downstream regulated gene 2; protein NDRG2; NDRG family member 2; NDRG1-related protein; N-myc downstream-regulated gene 2; antidepressant-related protein ADRG123;

• 1.Park S, Oh S S, Lee K W, et al. NDRG2 contributes to cisplatin sensitivity through modulation of BAK-to-Mcl-1 ratio. Cell Death & Disease, 2018, 9(2): 30.