Journal Article

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

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

2022

Overview

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 NEAT1 as a molecular trigger for ALYREF effects 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 fine-tunes the expression of the short NEAT1 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 NEAT1 .

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Animal models / Animals / Apoptosis / Biochemistry / Biomedical and Life Sciences / Biomedicine / Breast cancer / breast neoplasms / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / breasts / Carcinogenesis / Carcinogens / Cell Biology / cell growth / Cell Transformation, Neoplastic / Energy metabolism / Female / Gene regulation / Humans / Isoforms / Life Sciences / mechanism of action / Mice / Mitochondria / Mode of action / Molecular modelling / Nuclear Proteins - metabolism / Original / Original Article / Post-transcription / promoter regions / Protein Isoforms - genetics / Protein Isoforms - metabolism / Proteins / RNA Transport / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA-binding protein / RNA-binding proteins / RNA-Binding Proteins - metabolism / transcription (genetics) / Transcription Factors - metabolism / Tumorigenesis