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 () for further study， especially the most responsive isoform， _v4. We overexpressed _v4 under normoxia and performed microarray analysis to identify 108 _v4 regulated genes and their functions. Among these genes， we found that both mRNA expression and NDRG1 protein levels were inhibited by _v4. Finally， we used co-immunoprecipitation to show that _v4 destabilizes NDRG1 by promoting ubiquitin-mediated proteolysis. Our findings reveal a new type of epigenetic regulation of by _v4 in breast cancer cells.