Abstract
Abstract Hypoxia has been intensively investigated over past decades based on the observations that hypoxic tumors were more resistant to therapy and had a worse prognosis. Previously, we reported that N-myc downstream-regulated gene 1 (NDRG1) was strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuation of oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study is to identify the novel transcription factors that regulate NDRG1 and to investigate the functional roles of NDRG1 in hypoxia. In silico analysis predicted binding sites of aryl hydrocarbon receptor (AHR) existing in the NDRG1 promoter. Western blotting showed that nuclear AHR was up-regulated in the presence of cobalt and hypoxia. Immunofluorescence staining and chromatin immunoprecipitation assays showed that AHR translocated to nuclei and bound to NDRG1 promoter in hypoxia. Luciferase reporter assays further showed that the binding site of AHR at -412 ∼ -388 bp played a crucial role in regulating NDRG1 under hypoxia-mimicking conditions. Moreover, hypoxia-mimetic induction of NDRG1 by was attenuated by knockdown of AHR expression using short interfering RNA. Also, overexpression of AHR facilitated cell proliferation and migration via up-regulation of NDRG1, whereas shRNA knockdown of NDRG1 reduced cell growth and motility. In summary, these results showed for the first time that AHR positively regulates NDRG1 transcription through a AHR binding site by hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regime to prevent tumor malignancy under hypoxia. Citation Format: En-Yu Li, Wei-Yung Huang, Mong-Hsun Tsai, Eric Y. Chuang, Liang-Chuan Lai. Aryl hydrocarbon receptor activates NDRG1 transcription under hypoxia in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2015-1983
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