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.
MeSH terms
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A549 Cells
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Alternative Splicing*
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Animals
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Binding Sites
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Caco-2 Cells
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Cell Movement
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Epithelial-Mesenchymal Transition*
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Exons
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Female
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Gene Expression Regulation, Neoplastic
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Heterogeneous-Nuclear Ribonucleoproteins / genetics
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Heterogeneous-Nuclear Ribonucleoproteins / metabolism
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / secondary
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MCF-7 Cells
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Mice
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Neoplasm Invasiveness
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleic Acid Conformation
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Protein Binding
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RNA Interference
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RNA Precursors / chemistry
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RNA Precursors / genetics
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RNA Precursors / metabolism*
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RNA Splice Sites
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RNA, Long Noncoding / chemistry
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism*
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RNA, Messenger / chemistry
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RNA, Messenger / genetics
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RNA, Messenger / metabolism*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Signal Transduction
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Structure-Activity Relationship
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Transcription, Genetic
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Transfection
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Zinc Finger E-box-Binding Homeobox 1 / genetics
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Zinc Finger E-box-Binding Homeobox 1 / metabolism
Substances
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DNA-Binding Proteins
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Heterogeneous-Nuclear Ribonucleoproteins
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MIRN205 microRNA, human
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MicroRNAs
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Nuclear Proteins
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PCBP1 protein, human
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PPP1R10 protein, human
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RNA Precursors
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RNA Splice Sites
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RNA, Long Noncoding
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RNA, Messenger
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RNA-Binding Proteins
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1