title: Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival.
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.
authors.affiliation: Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.
authors.forename: H
authors.initials: H
authors.lastname: Choudhry
authors.affiliation: Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.|Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Albukhari
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Morotti
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Haider
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.
authors.forename: D
authors.initials: D
authors.lastname: Moralli
authors.affiliation: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Smythies
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schödel
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Green
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Camps
authors.affiliation: Old Road Campus Research Building, University of Oxford, Headington, Oxford, UK.
authors.forename: F
authors.initials: F
authors.lastname: Buffa
authors.affiliation: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington, Oxford, UK.
authors.forename: P
authors.initials: P
authors.lastname: Ratcliffe
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.|BSRC Alexander Fleming, Athens, Greece.
authors.forename: J
authors.initials: J
authors.lastname: Ragoussis
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Headington, Oxford, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Mole
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006801:Humans; D051379:Mice; D062085:RNA, Long Noncoding / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D062085:RNA, Long Noncoding; D011956:Receptors, Cell Surface; D000099162:Endothelial PAS Domain-Containing Protein 1; C407243:F11R protein, human; C577276:NEAT1 long non-coding RNA, human