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

• Published in: Oncogene 2015-08, Vol.34 (34), p.4482
• Main Authors: Choudhry, H, Albukhari, A, Morotti, M, Haider, S, Moralli, D, Smythies, J, Schödel, J, Green, C M, Camps, C, Buffa, F, Ratcliffe, P, Ragoussis, J, Harris, A L, Mole, D R
• Format: Article
• Language: English
• Subjects: Cancer; Cellular biology; Proteins; Ribonucleic acid; RNA; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.378

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.