Hypoxia drives glucose transporter 3 expression through HIF-mediated induction of the long non-coding RNA NICI
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Universitätsklinikum Erlangen, Germany.
- 3 University of Oxford Oxford, United Kingdom.
- NDM Research Building, University of Oxford, United Kingdom.
- Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Fahd Medical Research Centre, King Abdulaziz University, Saudi Arabia.
- Friedrich-Alexander-University Erlangen-Nürnberg, Germany.
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
- Target Discovery Institute, NDM Research Building, University of Oxford, United Kingdom.
- Department of Nephrology and Hypertension, Universitätsklinikum Erlangen, Germany.
Hypoxia inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long non-coding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long non-coding RNA NICI (Non-coding Intergenic Co-Induced transcript) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in multiple cell types. CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3). Knock-down or knock-out of NICI attenuated hypoxic induction of SLC2A3 indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR mediated activation of NICI expression. We also demonstrate that regulation of SLC2A3 is mediated through transcriptional activation rather than post-transcriptional mechanisms since knock-out of NICI leads to reduced recruitment of RNA polymerase 2 to the SLC2A3 promoter. Consistent with this we observe NICI-dependent regulation of glucose consumption and cell proliferation. Furthermore, NICI expression is regulated by the VHL tumour suppressor and is highly expressed in clear cell renal cancer, where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.
|Journal||The Journal of biological chemistry|
|Early online date||5 Nov 2019|
|Publication status||E-pub ahead of print - 5 Nov 2019|