Hypoxia can lead to solid tumor aggressiveness by driving multiple signaling pathways. Long non-coding RNAs respond to several extrinsic stimuli, causing changes in cancer cells by participating in multiple steps of gene expression. However, genomic profiling of long non-coding RNAs regulated by oxygen in breast cancer remained unclear. Therefore, the aims of this study were to identify oxygen-responsive long non-coding RNAs in breast cancer cells, and to delineate their regulatory mechanisms. The expression profiling of long non-coding RNAs in breast cancer cells growing under normoxic, hypoxic, and re-oxygenated conditions was examined using next-generation sequencing technology. Four hundred and seventy-two lncRNAs oxygen-responsive lncRNAs were identified. After examining the top three differentially expressed lncRNAs in hypoxia, we selected N-Myc Downstream Regulated Gene 1-Overlapping 1 (NDRG1-OT1) for further study, especially the most responsive isoform, NDRG1-OT1_v4. We overexpressed NDRG1-OT1_v4 under normoxia and performed microarray analysis to identify 108 NDRG1-OT1_v4 regulated genes and their functions. Among these genes, we found that both NDRG1 mRNA expression and NDRG1 protein levels were inhibited by NDRG1-OT1_v4. Finally, we used co-immunoprecipitation to show that NDRG1-OT1_v4 destabilizes NDRG1 by promoting ubiquitin-mediated proteolysis. Our findings reveal a new type of epigenetic regulation of NDRG1 by NDRG1-OT1_v4 in breast cancer cells.