LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS

Li Li, Pieter C van Breugel, Fabricio Loayza-Puch, Alejandro Pineiro Ugalde, Gozde Korkmaz, Naama Messika-Gold, Ruiqi Han, Rui Lopes, Eric P Barbera, Hans Teunissen, Elzo de Wit, Ricardo J Soares, Boye S Nielsen, Kim Holmstrøm, Dannys J Martínez-Herrera, Maite Huarte, Annita Louloupi, Jarno Drost, Ran Elkon, Reuven Agami

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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.

Originele taal-2Engels
Pagina's (van-tot)4213-4227
Aantal pagina's15
TijdschriftNucleic acids research
Nummer van het tijdschrift8
StatusGepubliceerd - 4 mei 2018
Extern gepubliceerdJa


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