LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS. Issue 8 (22nd February 2018)

• Record Type: Journal Article
• Authors: Li, Li; van Breugel, Pieter C; Loayza-Puch, Fabricio; Ugalde, Alejandro Pineiro; Korkmaz, Gozde; Messika-Gold, Naama; Han, Ruiqi; Lopes, Rui; Barbera, Eric P; Teunissen, Hans; de Wit, Elzo; Soares, Ricardo J; Nielsen, Boye S; Holmstrøm, Kim; Martínez-Herrera, Dannys J; Huarte, Maite; Louloupi, Annita; Drost, Jarno; Elkon, Ran; Agami, Reuven
• Is Part Of: Nucleic acids research. Volume 46:Issue 8(2018)
• Page Start: 4213
• Page End: 4227
• Publication Date: 2018-02-22
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky087
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Oncogene-induced senescence (OIS), provoked in response to oncogenic activation, is considered an important tumor suppressor mechanism. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt without a protein-coding capacity. Functional studies showed that deregulated lncRNA expression promote tumorigenesis and metastasis and that lncRNAs may exhibit tumor-suppressive and oncogenic function. Here, we first identified lncRNAs that were differentially expressed between senescent and non-senescent human fibroblast cells. Using RNA interference, we performed a loss-function screen targeting the differentially expressed lncRNAs, and identified lncRNA-OIS1 (lncRNA#32, AC008063.3 or ENSG00000233397) as a lncRNA required for OIS. Knockdown of lncRNA-OIS1 triggered bypass of senescence, higher proliferation rate, lower abundance of the cell-cycle inhibitor CDKN1A and high expression of cell-cycle-associated genes. Subcellular inspection of lncRNA-OIS1 indicated nuclear and cytosolic localization in both normal culture conditions as well as following oncogene induction. Interestingly, silencing lncRNA-OIS1 diminished the senescent-associated induction of a nearby gene (Dipeptidyl Peptidase 4, DPP4) with established role in tumor suppression. Intriguingly, similar to lncRNA-OIS1, silencing DPP4 caused senescence bypass, and ectopic expression of DPP4 in lncRNA-OIS1 knockdown cells restored the senescent phenotype. Thus, our data indicate that lncRNA-OIS1 links oncogenic induction and senescence with the activation of the tumor suppressor DPP4.