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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https://hdl.handle.net/10037/27596Date
2022-07-01Type
Journal articleTidsskriftartikkel
Peer reviewed
Author
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, Seyed Mohammad; Perander, Maria; Barbano, Raffaela; Graier, Wolfgang F.; Parrella, Paola; Calin, George Adrian; Pichler, MartinAbstract
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 identifed high ALYREF
expression as a factor for poor survival in breast cancer patients. ALYREF signifcantly infuenced cellular growth, apoptosis
and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profling, phenocopy and rescue experiments identifed the short isoform of the lncRNA NEAT1 as a molecular
trigger for ALYREF efects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 promoter region
to enhance the global NEAT1 transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates
the post-transcriptional generation of the short isoform of NEAT1, as well as by direct binding and stabilization of the short
isoform of NEAT1, ALYREF selectively fne-tunes the expression of the short NEAT1 isoform. Overall, our study describes
ALYREF as a novel factor contributing to breast carcinogenesis and identifes novel molecular mechanisms of regulation
the two isoforms of NEAT1.
Publisher
SpringerCitation
Klec, Knutsen, Schwarzenbacher, Jonas, Pasculli, Heitzer, Rinner, Krajina, Prinz, Gottschalk, Ulz, Deutsch, Prokesch, Jahn, Lellahi, Perander, Barbano, Graier, Parrella, Calin, Pichler. ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform. Cellular and Molecular Life Sciences (CMLS). 2022;79(7)Metadata
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