Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 36, Issue 10, Pages 1480-1493Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01096-15
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Funding
- Fondation Coeur et Arteres (FCA) [FCA R09038AA]
- Fondation de France [FDF U1081]
- Agence Nationale de la Recherche (ANR) [RPV12004AAA]
- Agence Nationale de la Recherche (ANR) through the Investments for the Future Labex Signalife Program [ANR-11-LABX-0028-01]
- Fondation ARC pour la Recherche sur le Cancer (ARC) [R13026AA-ARC]
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RNA activation (RNAa) is a gene regulation process in which promoter-targeted short double-stranded RNAs (dsRNAs) or microRNAs (miRs) induce target gene expression at the transcriptional level. Here, we investigate the presence of cryptic promoter transcripts within the VEGF promoter. Single-strand sense and antisense noncoding vascular endothelial growth factor (NcVEGF) promoter transcripts are identified, and their respective expression is studied in cells transfected with a VEGF promoter targeted dsRNA, namely, dsVEGF706, in hypoxic cells and in human malignant lung tissues. Interestingly, in dsVEGF706-transfected, as well as in hypoxic cells, NcVEGF expression levels increase coordinately with coding VEGF expression. Ago2 interaction with both sense and antisense NcVEGFs is increased in hypoxic cells, whereas in dsVEGF706-transfected cells, Ago2 and the antisense strand of the dsRNA interact specifically with the sense NcVEGF transcript. Furthermore, both dsVEGF706 and ectopic NcVEGF transcripts are able to activate the VEGF promoter endogenously present or in a reporter construct. Finally, using small interfering RNA targeting Ago2, we show that RNAa plays a role in the maintenance of increased VEGF and NcVEGF expression after hypoxia. Given the central role of VEGF in major human diseases, including cancer, this novel molecular mechanism is poised to reveal promising possibilities for therapeutic interventions.
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