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Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Natl Canc Ctr, Dept Syst Canc Sci, Grad Sch Canc Sci & Policy, 323 Ilsan Ro, Goyang Si 10408, South Korea..
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2017 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 487Article in journal (Refereed) Published
Abstract [en]

Background: The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells.

Methods: We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling.

Results: Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers.

Conclusions: Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD , 2017. Vol. 17, article id 487
Keyword [en]
Cancer, DIP2C, Gene knockout, rAAV-mediated gene targeting, Tumour cell biology, DNA methylation, Epithelial-mesenchymal transition (EMT)
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-331232DOI: 10.1186/s12885-017-3472-5ISI: 000405865300001PubMedID: 28716088OAI: oai:DiVA.org:uu-331232DiVA, id: diva2:1149461
Funder
Swedish Cancer Society, 2006/2154, 2007/775, 2012/834, 2012/1235Swedish Foundation for Strategic Research , F06-0050, RBa08-0114Swedish Society for Medical Research (SSMF)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved

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