1. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression.
- Author
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Grelet S, Link LA, Howley B, Obellianne C, Palanisamy V, Gangaraju VK, Diehl JA, and Howe PH
- Subjects
- A549 Cells, Animals, Binding Sites, Breast Neoplasms genetics, Breast Neoplasms pathology, Caco-2 Cells, Cell Movement, DNA-Binding Proteins genetics, Exons, Female, Gene Expression Regulation, Neoplastic, Heterogeneous-Nuclear Ribonucleoproteins genetics, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Humans, Lung Neoplasms genetics, Lung Neoplasms secondary, MCF-7 Cells, Mice, MicroRNAs genetics, MicroRNAs metabolism, Neoplasm Invasiveness, Nuclear Proteins genetics, Nucleic Acid Conformation, Protein Binding, RNA Interference, RNA Precursors chemistry, RNA Precursors genetics, RNA Splice Sites, RNA, Long Noncoding chemistry, RNA, Long Noncoding genetics, RNA, Messenger chemistry, RNA, Messenger genetics, RNA-Binding Proteins genetics, Signal Transduction, Structure-Activity Relationship, Transcription, Genetic, Transfection, Zinc Finger E-box-Binding Homeobox 1 genetics, Zinc Finger E-box-Binding Homeobox 1 metabolism, Alternative Splicing, Breast Neoplasms metabolism, DNA-Binding Proteins metabolism, Epithelial-Mesenchymal Transition, Lung Neoplasms metabolism, Nuclear Proteins metabolism, RNA Precursors metabolism, RNA, Long Noncoding metabolism, RNA, Messenger metabolism, RNA-Binding Proteins metabolism
- Abstract
The contribution of lncRNAs to tumour progression and the regulatory mechanisms driving their expression are areas of intense investigation. Here, we characterize the binding of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) to a nucleic acid structural element located in exon 12 of PNUTS (also known as PPP1R10) pre-RNA that regulates its alternative splicing. HnRNP E1 release from this structural element, following its silencing, nucleocytoplasmic translocation or in response to TGFβ, allows alternative splicing and generates a non-coding isoform of PNUTS. Functionally the lncRNA-PNUTS serves as a competitive sponge for miR-205 during epithelial-mesenchymal transition (EMT). In mesenchymal breast tumour cells and in breast tumour samples, the expression of lncRNA-PNUTS is elevated and correlates with levels of ZEB mRNAs. Thus, PNUTS is a bifunctional RNA encoding both PNUTS mRNA and lncRNA-PNUTS, each eliciting distinct biological functions. While PNUTS mRNA is ubiquitously expressed, lncRNA-PNUTS appears to be tightly regulated dependent on the status of hnRNP E1 and tumour context.
- Published
- 2017
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