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Oncogene. 2015 Aug 20;34(34):4482-90. doi: 10.1038/onc.2014.378. Epub 2014 Nov 24.

Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival.

Author information

1
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
2
The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.
3
Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, UK.
4
The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington, Oxford, UK.
5
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
6
Old Road Campus Research Building, University of Oxford, Headington, Oxford, UK.
7
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
8
BSRC Alexander Fleming, Athens, Greece.

Abstract

Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.

PMID:
25417700
PMCID:
PMC4430310
DOI:
10.1038/onc.2014.378
[Indexed for MEDLINE]
Free PMC Article

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