Hypoxia drives glucose transporter 3 expression through hypoxia-inducible transcription factor (HIF)-mediated induction of the long noncoding RNA NICI

Lauer V, Grampp S, Platt J, Lafleur V, Lombardi O, Choudhry H, Kranz F, Hartmann A, Wullich B, Yamamoto A, Coleman ML, Ratcliffe PJ, Mole DR, Schödel J (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 295

Pages Range: 4065-4078

Journal Issue: 13

DOI: 10.1074/jbc.RA119.009827

Abstract

Hypoxia-inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long noncoding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long noncoding RNA Noncoding Intergenic Co-Induced transcript (NICI) 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). Knockdown or knockout 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 posttranscriptional mechanisms because knockout 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 von Hippel-Lindau (VHL) tumor suppressor and is highly expressed in clear cell renal cell carcinoma (ccRCC), where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

University of Oxford United Kingdom (GB) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) University of Birmingham United Kingdom (GB)

How to cite

APA:

Lauer, V., Grampp, S., Platt, J., Lafleur, V., Lombardi, O., Choudhry, H.,... Schödel, J. (2020). Hypoxia drives glucose transporter 3 expression through hypoxia-inducible transcription factor (HIF)-mediated induction of the long noncoding RNA NICI. Journal of Biological Chemistry, 295(13), 4065-4078. https://doi.org/10.1074/jbc.RA119.009827

MLA:

Lauer, Victoria, et al. "Hypoxia drives glucose transporter 3 expression through hypoxia-inducible transcription factor (HIF)-mediated induction of the long noncoding RNA NICI." Journal of Biological Chemistry 295.13 (2020): 4065-4078.

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