The hypoxia-responsive lncRNA NDRG-OT1 promotes NDRG1 degradation via ubiquitin-mediated proteolysis in breast cancer cells
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Hsin-Chen Lin1, Ching-Ching Yeh1, Lo-Yun Chao2, Mong-Hsun Tsai2,3, Hung-Hsin Chen3, Eric Y. Chuang3,4 and Liang-Chuan Lai1,3
1Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan
2Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
3Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan
4Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
Liang-Chuan Lai, email: [email protected]
Keywords: hypoxia; lncRNA; NDRG1-OT1; NDRG1; ubiquitination
Received: November 23, 2016 Accepted: December 18, 2017 Published: December 28, 2017
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.
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