Faculty, Staff and Student Publications
Publication Date
7-1-2022
Journal
Cellular and Molecular Life Sciences
Abstract
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.
Keywords
Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Female, Humans, Mice, Nuclear Proteins, Protein Isoforms, RNA Transport, RNA, Long Noncoding, RNA-Binding Proteins, Transcription Factors, Breast cancer, ALYREF, Transcriptional regulation, lncRNA, NEAT1
DOI
10.1007/s00018-022-04402-2
PMID
35776213
PMCID
PMC9249705
PubMedCentral® Posted Date
7-1-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Medical Cell Biology Commons, Oncology Commons