Abstract
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.
Highlights
Hypoxia is a crucial determinant of the aggressiveness of solid tumors [1]
In order to examine all Long non-coding RNAs (lncRNAs) regulated by O2 in MCF-7 cells, cells were harvested under normoxia (O2), hypoxia (N2), and re-oxygenation (Re-O2) conditions in triplicate
To identify oxygen-responsive lncRNAs in breast cancer, we identified 472 lncRNAs responding to changes in oxygen concentration
Summary
Hypoxia is a crucial determinant of the aggressiveness of solid tumors [1]. Because of the rapid growth of tumor cells and inadequate vascular distribution in the tumor microenvironment, an imbalance in oxygen delivery and consumption results in hypoxia [2, 3]. Previous studies have shown that hypoxia can affect the proliferation, invasion, and metastasis of tumors [4, 5], the induction of apoptosis [6], and angiogenesis [7]. Tumors become more aggressive as a result. N-myc downstream-regulated gene 1 (NDRG1) has various effects on tumor cell function. It has been reported to respond to many stressful environments, such as DNA damage [8] and hypoxia [9, 10]. Up-regulation of NDRG1 leads to cellular differentiation, proliferation, re-distribution of the cell cycle, and metastasis [11,12,13]. No studies have indicated that NDRG1 is regulated by DNA methylation or non-coding RNA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
