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Klec, Christiane; Knutsen, Erik; Schwarzenbacher, Daniela; Jonas, Katharina; Pasculli, Barbara; Heitzer, Ellen; Rinner, Beate; Krajina, Katarina; Prinz, Felix; Gottschalk, Benjamin; Ulz, Peter; Deutsch, Alexander; Prokesch, Andreas; Jahn, Stephan W.; Lellahi, S. Mohammad; Perander, Maria; Barbano, Raffaela; Graier, Wolfgang F.; Parrella, Paola; Calin, George Adrian; Pichler, Martin

ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform

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  • Media type: E-Article
  • Title: ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform
  • Contributor: Klec, Christiane; Knutsen, Erik; Schwarzenbacher, Daniela; Jonas, Katharina; Pasculli, Barbara; Heitzer, Ellen; Rinner, Beate; Krajina, Katarina; Prinz, Felix; Gottschalk, Benjamin; Ulz, Peter; Deutsch, Alexander; Prokesch, Andreas; Jahn, Stephan W.; Lellahi, S. Mohammad; Perander, Maria; Barbano, Raffaela; Graier, Wolfgang F.; Parrella, Paola; Calin, George Adrian; Pichler, Martin
  • imprint: Springer Science and Business Media LLC, 2022
  • Published in: Cellular and Molecular Life Sciences
  • Language: English
  • DOI: 10.1007/s00018-022-04402-2
  • ISSN: 1420-682X; 1420-9071
  • Keywords: Cell Biology ; Cellular and Molecular Neuroscience ; Pharmacology ; Molecular Biology ; Molecular Medicine
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA<jats:italic>NEAT1</jats:italic>as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the<jats:italic>NEAT1</jats:italic>promoter region to enhance the global<jats:italic>NEAT1</jats:italic>transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of<jats:italic>NEAT1</jats:italic>, as well as by direct binding and stabilization of the short isoform of<jats:italic>NEAT1,</jats:italic>ALYREF selectively fine-tunes the expression of the short<jats:italic>NEAT1</jats:italic>isoform. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of<jats:italic>NEAT1</jats:italic>.</jats:p>