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

Autor:	Li L; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., van Breugel PC; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Loayza-Puch F; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Ugalde AP; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Korkmaz G; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Messika-Gold N; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, 69978, Tel Aviv University, Tel Aviv, Israel., Han R; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Lopes R; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Barbera EP; Division of Molecular Genetics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Teunissen H; Division of Gene Regulation, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., de Wit E; Division of Gene Regulation, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Soares RJ; Bioneer A/S, Kogle Allé 2, DK-2970 Hørsholm, Denmark., Nielsen BS; Bioneer A/S, Kogle Allé 2, DK-2970 Hørsholm, Denmark., Holmstrøm K; Bioneer A/S, Kogle Allé 2, DK-2970 Hørsholm, Denmark., Martínez-Herrera DJ; Institute of Health Research of Navarra (IdiSNA), 31008 Pamplona, Spain., Huarte M; Institute of Health Research of Navarra (IdiSNA), 31008 Pamplona, Spain., Louloupi A; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Drost J; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands., Elkon R; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, 69978, Tel Aviv University, Tel Aviv, Israel., Agami R; Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.; Erasmus MC, Rotterdam University, 3000 CA Rotterdam, The Netherlands.; Oncode institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2018 May 04; Vol. 46 (8), pp. 4213-4227.
DOI:	10.1093/nar/gky087
Abstrakt:	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.
Databáze:	MEDLINE
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