Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition


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

                  <p>We engineered human <em>DIP2C</em> 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 <em>DIP2C</em>. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling.</p> 

                  <p>Knockout of <em>DIP2C</em> 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 <em>DIP2C</em>, including the tumour-suppressor encoding <em>CDKN2A</em> gene, the epithelial-mesenchymal transition (EMT) regulator-encoding <em>ZEB1</em>, and <em>CD44</em> and <em>CD24</em> 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 <em>DIP2C</em>. 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 <em>DIP2C</em> knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers.</p> 

                  <p>Loss of <em>DIP2C</em> triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.</p> 
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