Grelet Simon, Link Laura A, Howley Breege, Obellianne Clémence, Palanisamy Viswanathan, Gangaraju Vamsi K, Diehl J Alan, Howe Philip H
Department of Biochemistry, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Nat Cell Biol. 2017 Sep;19(9):1105-1115. doi: 10.1038/ncb3595. Epub 2017 Aug 21.
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.
长链非编码RNA（lncRNA）对肿瘤进展的贡献以及驱动其表达的调控机制是当前深入研究的领域。在此，我们描述了异质性核核糖核蛋白E1（hnRNP E1）与位于PNUTS（也称为PPP1R10）前体RNA第12外显子中的一个核酸结构元件的结合，该元件调节其可变剪接。在hnRNP E1沉默、核质转运或对转化生长因子β（TGFβ）作出反应后，其从该结构元件上释放，从而允许可变剪接并生成PNUTS的一种非编码异构体。在功能上，lncRNA-PNUTS在上皮-间质转化（EMT）过程中作为miR-205的竞争性海绵。在间充质乳腺肿瘤细胞和乳腺肿瘤样本中，lncRNA-PNUTS的表达升高，且与ZEB mRNA的水平相关。因此，PNUTS是一种双功能RNA，编码PNUTS mRNA和lncRNA-PNUTS，各自发挥不同的生物学功能。虽然PNUTS mRNA广泛表达，但lncRNA-PNUTS的表达似乎依赖于hnRNP E1的状态和肿瘤背景而受到严格调控。
