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.
Highlights
Metazoan cells maintain oxygen homeostasis through a balance between mitochondrial oxygen consumption and external oxygen supply
We first examined the temporal patterns of N-myc downstream-regulated gene 3 (NDRG3) and hypoxia-inducible factors (HIFs)-1/2α expression during hypoxia
2α expression preceded NDRG3 expression and that NDRG3 expression preceded a gradual decline of HIF-1/ 2α
Summary
Metazoan cells maintain oxygen homeostasis through a balance between mitochondrial oxygen consumption and external oxygen supply. Disruption of this balance results in energy depletion or oxidative injury, which may lead to various diseases including cancer[1]. In addition to the oxygen-dependent regulation, HIF-1α expression is determined at the translational step, which is activated by the PI3K–AKT–mTOR pathway. This pathway is highly activated in prostate cancer cells because of the deletion of the PTEN gene, so HIF-1α is frequently overexpressed in prostate cancer[11,12]
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