DEK over-expression promotes mitotic defects and micronucleus formation

Abstract

The DEK gene encodes a nuclear protein that binds chromatin and is involved in various fundamental nuclear processes including transcription, RNA splicing, DNA replication and DNA repair. Several cancer types characteristically over-express DEK at the earliest stages of transformation. In order to explore relevant mechanisms whereby DEK supports oncogenicity, we utilized cancer databases to identify gene transcripts whose expression patterns are tightly correlated with that of DEK. We identified an enrichment of genes involved in mitosis and thus investigated the regulation and possible function of DEK in cell division. Immunofluorescence analyses revealed that DEK dissociates from DNA in early prophase and re-associates with DNA during telophase in human keratinocytes. Mitotic cell populations displayed a sharp reduction in DEK protein levels compared to the corresponding interphase population, suggesting DEK may be degraded or otherwise removed from the cell prior to mitosis. Interestingly, DEK overexpression stimulated its own aberrant association with chromatin throughout mitosis. Furthermore, DEK colocalized with anaphase bridges, chromosome fragments, and micronuclei, suggesting a specific association with mitotically defective chromosomes. We found that DEK over-expression in both non-transformed and transformed cells is sufficient to stimulate micronucleus formation. These data support a model wherein normal chromosomal clearance of DEK is required for maintenance of high fidelity cell division and chromosomal integrity. Therefore, the overexpression of DEK and its incomplete removal from mitotic chromosomes promotes genomic instability through the generation of genetically abnormal daughter cells. Consequently, DEK over-expression may be involved in the initial steps of developing oncogenic mutations in cells leading to cancer initiation

Dek overexpression in murine epithelia increases overt esophageal squamous cell carcinoma incidence

“…In the Bi-L-Dek_K5-tTA mouse model, Dek overexpression at the message and protein level was approximately 2–4 fold over that of endogenous Dek. This relatively modest level is in agreement with other published studies suggesting DEK expression levels are tightly regulated [ 1 , 16 , 58 , 77 – 79 ]. Achieving strong overexpression of DEK in vitro in our hands has been notoriously difficult, potentially due to toxicity and cell death, e. g. in the above Drosophila study [ 88 ].…”

“…Importantly, a modest level of DEK overexpression in epithelial cells has been linked to oncogenic phenotypes in vitro . These DEK dependent oncogenic activities include enhanced cancer stem cell growth, colony formation, cellular invasion, mitotic abnormalities, and metabolic de-regulation, providing evidence that subtle increases in DEK protein expression are sufficient to elicit significant cellular consequences [ 16 , 77 – 79 ]. In human ESCC, HNSCC, breast, bladder, colorectal, hepatocellular, and non-small cell lung carcinoma, DEK protein levels were increased in tumor versus adjacent normal tissue, and the extent of overexpression was variable.…”

Neuroanatomical Distribution of DEK Protein in Corticolimbic Circuits Associated with Learning and Memory in Adult Male and Female Mice

“…Consistent with DEK overexpression in tumors or proliferating cells, these factors are also expressed at higher rates in cancer (Privette Vinnedge et al 2011) and are associated with either cellular or behavioral indices of learning and memory (Aubry et al 2015, Bean et al 2014, Gurtner et al 2010, Rossner et al 2006, Ting et al 2014, Vierk et al 2014). While DEK is known for its role in cancer and autoimmune diseases (Matrka et al 2015, Mor-Vaknin et al 2011, Pease et al 2015), its function in the CNS has not been described. DEK mRNA expression has been reported in mouse (http://www.brain-map.org/) and human brains (Kroes et al 2000), but to our knowledge, no studies have investigated protein expression nor neuroanatomical distribution in distinct brain regions.…”

“…For example, cancer is associated with increased cellular proliferation (Stopper et al 2003), decreased apoptosis (Gerl & Vaux 2005), up-regulation of the canonical Wnt-pathway (Segditsas & Tomlinson 2006, Zhan et al 2017), while Alzheimer’s disease is associated with DNA damage (Coppede & Migliore 2009, Lovell & Markesbery 2007), decreased neurogenesis (Demars et al 2010), apoptosis (Smale et al 1995), and down-regulation of the canonical Wnt-pathway (Riise et al 2015). DEK deficiency in vitro or in the periphery induces cellular and molecular anomalies commonly observed in neurodegenerative diseases including DNA damage, cellular senescence, decreased cellular proliferation, and down-regulation of the canonical Wnt-pathway (Kavanaugh et al 2011, Matrka et al 2015, Saha et al 2013, Tabbert et al 2006). In this same vein, DEK expression facilitates DNA repair, is anti-apoptotic (through p53 dependent and independent mechanisms), promotes cellular proliferation, and prevents differentiation (Wise-Draper et al 2006, Wise-Draper et al 2009b).…”

The nuclear DEK interactome supports multi‐functionality

“…Since this discovery, DEK has been classified as an oncoprotein and shown to be overexpressed in many diverse tumor types, wherein the degree of overexpression was linked to worse prognosis, advanced stage tumors, and chemotherapy resistance . Cellular functions of the oncoprotein include activities in modifying chromatin structure, histone chaperoning, epigenetic modification and transcription regulation, mRNA splicing, DNA repair, DNA replication fork restart, mitotic non‐disjunction events, evasion of senescence and apoptosis, proliferation cancer stem cell fitness and invasion, inflammation, and metabolic reprogramming . Precise molecular mechanisms whereby DEK regulates these cellular processes remain unclear in many cases.…”