Aryl Hydrocarbon Receptor Activates NDRG1 Transcription under Hypoxia in Breast Cancer Cells

Hypoxia has been intensively investigated over the past several decades based on the observations that hypoxic tumors are more resistant to therapy and have a worse prognosis. Previously, we reported that N-myc downstream-regulated gene 1 (NDRG1) is strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuating oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study was to identify the transcription factors that regulate NDRG1 and to investigate the functional roles of NDRG1 in hypoxia. We showed that binding sites of aryl hydrocarbon receptor (AHR) were predicted in the NDRG1 promoter. Nuclear AHR was up-regulated in the presence of cobalt and hypoxia. AHR translocated to nuclei and bound between base pairs -412 and -388 of the NDRG1 promoter in hypoxia. Moreover, hypoxia-mimetic induction of NDRG1 was attenuated by knockdown of AHR expression. Also, overexpression of AHR facilitated cell proliferation and migration via up-regulation of NDRG1. These results showed for the first time that AHR positively regulates NDRG1 transcription through an AHR binding site by way of hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regimen to prevent tumor malignancy under hypoxia.