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

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