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NDRG2 is a new HIF-1 Target Gene Necessary for Hypoxia-Induced Apoptosis in A549 CellsWang L.1,3,* · Liu N.1,3,* · Yao L.1,3 · Li F.1,3 · Zhang J.1,3 · Deng Y.1 · Liu J.1,3 · Ji S.1,3 · Yang A.3 · Han H.3 · Zhang Y.2,3 · Zhang J.1,3 · Han W.2,3 · Liu X.1,3
1Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an,2Biotechnology Center, The Fourth Military Medical University and3The State Key Laboratory of Cancer Biology, Xi’an,*These authors equally contributed to this paper Corresponding Author
Xinping Liu, Department of Biochemistry and Molecular Biology
Wei Han, Biotechnology CenterThe Fourth Military Medical University
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The NDRG2 gene belongs to a family of N-Myc downstream-regulated genes (NDRGs) and is expressed in many normal tissues. NDRG2 gene expression has been shown to be regulated in the stress response of certain cells. However, its function is not yet fully understood. Many studies have demonstrated that hypoxia, one of the stress responses, induced apoptosis in several cell types. In the current study, we investigated NDRG2 involvement in hypoxia response and found that NDRG2 expression was markedly up-regulated in several tumor cell lines exposed to hypoxic conditions or similar stresses at the mRNA and protein level. We also observed that the expression of NDRG2 was regulated by Hypoxia-inducible factor 1 (HIF-1) in tumor cells under hypoxia. Three hypoxia-responsive elements (HREs) in the NDRG2 promoter were identified. HRE1 could directly bind Hif-1 in vivo. Importantly, we found that silencing or enforcing the expression of NDRG2 could strongly inhibit or increase apoptosis. In addition, our data also showed that Ndrg2 was able to be translocated from the cytoplasm to the nucleus, and the segment from 101 to 178 amino acids of Ndrg2 is responsible for its translocation. Taken together, this study suggests that NDRG2 is a Hif-1 target gene and closely related with hypoxia-induced apoptosis in A549 cells.
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