Stacking the DEK: From chromatin topology to cancer stem cells

Vinnedge, Lisa M. Privette; Kappes, Ferdinand; Nassar, Nicolas; Wells, Susanne I.

doi:10.4161/cc.23121

Cited by 60 publications

(53 citation statements)

References 158 publications

(219 reference statements)

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“…Remarkable is also the series of histone modification editors ANKRDs, whose genes are down-regulated in SetA. Among the chromatin modifiers, we find Dek , up-regulated in Set A and also up-regulated in group 4 MB (Hooper et al, 2014), which is a known oncogene that can confer stem cell-like qualities and is thus potentially enhancing the probability of cancer (Privette Vinnedge et al, 2013). Altogether, the alteration in Set A of genes involved in histone modification and chromatin remodeling fits with the idea that the ablation of Tis21 may reduce in the Tis21 -null GCPs the restraint toward a lineage shift, as exposed in the previous section.…”

Section: Discussionmentioning

confidence: 84%

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Gentile¹,

Ceccarelli²,

Micheli³

et al. 2016

Front. Pharmacol.

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We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/−/Tis21KO). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+/−/Tis21 wild-type vs. Ptch1+/−/Tis21 knockout), among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. The data analysis using bioinformatic tools revealed: (i) a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; (ii) a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype, i.e., the neural cell type involved in group 3 MB; (iii) the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

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Section: Discussionmentioning

confidence: 84%

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Gentile¹,

Ceccarelli²,

Micheli³

et al. 2016

Front. Pharmacol.

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“…1C). DEK is a putative oncoprotein, first described as a fusion gene in an aggressive subset of acute myeloid leukemia (12-14). This finding therefore raised the possibility that DEK might represent an SPOP substrate that becomes dysregulated by oncogenic prostate cancer SPOP mutations.…”

mentioning

confidence: 99%

“…DEK has also been implicated in the maintenance of stem cell-like properties, such as sphere formation under non-adherent culture conditions (14, 18-20). Consistent with these observations, SPOP-Y87N produced elevated DEK levels and enhanced sphere formation in primary human prostate epithelial cells (hPREC, Fig.…”

mentioning

confidence: 99%

Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

Theurillat

Udeshi

Errington

et al. 2014

Science

207

224

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Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, implicating DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

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“…26,27,[38][39][40] Such modifications alter its ability to bind chromatin, re-localize, and carry out specific biological functions in a manner that remain poorly understood and have been studied primarily in cancer cells wherein DEK is over-expressed. 41 For example, DEK is phosphorylated by CK2 during interphase and phosphorylation levels appear to peak in G1. 38 In vitro, CK2 phosphorylation reduces the affinity of DEK for DNA and increases DEK self-multimerization.…”

Section: Introductionmentioning

confidence: 99%

DEK over-expression promotes mitotic defects and micronucleus formation

Matrka

Hennigan

Kappes³

et al. 2015

Cell Cycle

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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

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Stacking the DEK: From chromatin topology to cancer stem cells

Cited by 60 publications

References 158 publications

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

DEK over-expression promotes mitotic defects and micronucleus formation

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