NDRG3 lowers the metastatic potential in prostate cancer as a feedback controller of hypoxia-inducible factors

Abstract

Expression of hypoxia-inducible factors (HIFs) and N-myc downstream-regulated gene 3 (NDRG3) are oxygen-dependently regulated by prolyl hydroxylase domain (PHD) enzymes. Little is known about the role of NDRG3 in the cellular adaptation to hypoxia, whereas the roles of HIFs are well understood. In this study, we investigated how NDRG3 affects the hypoxic response in prostate cancer cells. Compared with HIF-1α, hypoxic induction of NDRG3 was observed at a later phase. NDRG3 reduced hypoxic expression of HIF-1α by inhibiting AKT-driven translation of HIF1A mRNA. In addition, NDRG3 functionally inhibited HIF-1 by dissociating the coactivator p300 from HIF-1α. Accordingly, NDRG3 may fine-tune the HIF-1 signaling pathway to cope with long-term hypoxia. Of the diverse effects of HIF-1α on cancer progression, hypoxia-induced cell migration was investigated. In transwell chambers, NDRG3 negatively regulated the migration and invasion of prostate cancer cells under hypoxia. An informatics analysis using Gene Expression Omnibus (GEO) revealed that NDRG3 downregulation is associated with prostate cancer metastasis and high expression of HIF-1 downstream genes. In cancer tissue arrays, NDRG3 expression was lower in prostate cancer tissues with a Gleason score of 8 or greater and was inversely correlated with HIF-1α expression. Therefore, NDRG3 may have an anti-metastatic function in prostate cancer under a hypoxic microenvironment. A protein activated under the low oxygen conditions typical of tumor surroundings has an anti-metastatic function in prostate cancer cells. Jong-Wan Park and colleagues from Seoul National University College of Medicine, South Korea, showed in prostate cancer cells that NDRG3, a protein activated under low oxygen conditions, works to fine-tune the signaling of another oxygen-sensitive protein to deal with the long-term stress imposed by cellular conditions. As a consequence, migration and invasion of prostate cancer cells are repressed. The researchers then looked at NDRG3 expression levels in tissue samples from men with prostate cancer and found that the more aggressive the disease the lower the NDRG3 activity. The results point to NDRG3 as a tumor suppressor in prostate cancer and suggest drug strategies designed to boost its function could aid in the treatment of this disease.