Aryl Hydrocarbon Receptor Regulates NDRG1 Transcription under Hypoxia Mimic Conditions

• Main Authors: En-Yu Li, 李恩宇
• Other Authors: Liang-Chuan Lai
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/35803979728372662164

碩士 === 國立臺灣大學 === 生理學研究所 === 101 === Hypoxia has been intensively investigated over the past decades based on the observations that hypoxic tumors were more resistant to therapy and had a worse prognosis. Previously, our lab identified 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 upon changes in oxygen concentrations. First of all, bioinformatic tools, MatInspector and MatchTM 1.0, were used to search the DNA binding sites of transcription factors in the promoter of NDRG1. Based on the similarities and numbers of transcription factor binding sites existing in the NDRG1 promoter (-783 ~ +312 bp), aryl hydrocarbon receptor (AHR) was identified as the most potential candidate and herein chosen for further validation. Western blotting showed that nuclear AHR was up-regulated in the presence of cobalt and hypoxia. Luciferase reporter assays showed that binding site of AHR at -402 ~ -398 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. In summary, these results showed for the first time that AHR positively regulates NDRG1 transcription through a putative AHR binding site in the promoter by hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regime to prevent tumor malignancy under hypoxia.