Research IndicatorsGraph generated 16 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
TICdb, Universidad de Navarra
Search the database of Translocation breakpoints In Cancer for "DEK"
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: DEK (cancer-related)
Qiao MX, Li C, Zhang AQ, et al.Regulation of DEK expression by AP-2α and methylation level of DEK promoter in hepatocellular carcinoma.
Oncol Rep. 2016; 36(4):2382-90 [PubMed
] Related Publications
DEK is overexpressed in multiple invasive tumors. However, the transcriptional regulatory mechanism of DEK remains unclear. In the present study, progressive-type truncation assay indicated that CpG2-2 (-167 bp/+35 bp) was the DEK core promoter, whose methylation inhibited DEK expression. Bisulfite genomic sequencing analysis indicated that the methylation levels of the DEK promoter in normal hepatic cells and tissues were higher than those in hepatocellular carcinoma (HCC) cells. TFSEARCH result revealed transcription factor binding sites in CpG2-2. Among the sites, the AP-2α binding site showed the most significant methylation difference; hence, AP-2α is a key transcription factor that regulates DEK expression. Point or deletion mutation of the AP-2α binding site significantly reduced the promoter activity. Chromatin immunoprecipitation assay demonstrated the binding of AP-2α to the core promoter. Furthermore, knock down of endogenous AP-2α downregulated DEK expression, whereas overexpression of AP-2α upregulated DEK expression. Thus, AP-2α is an important transcription factor of DEK expression, which is correlated with the methylation level of the DEK core promoter in HCC.
BACKGROUND: While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes.
METHODS: We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310).
RESULTS: Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades.
INTERPRETATION: Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.
MicroRNAs (miRNAs) are classes of small, non-coding RNAs that regulate the translation of target mRNA transcripts. In this study, we demonstrated that miR-592 was downregulated in human hepatocellular carcinoma (HCC) and could suppress growth of the human HCC cell line HepG2. A tumor oncogene, DEK, was identified as a direct target of miR-592. Luciferase report assay indicated miR-592 regulates DEK expression though bind to its 3'UTR. Furthermore, knockdown of DEK also suppressed cell proliferation of HepG2 cells, which was consist with miR-592. At last, we suggested that DEK was upregulated in HCC tissues inversely with miR-592. These results demonstrated that miR-592 targets DEK transcript and suppresses HCC cell growth, and may provide potential therapeutic target in human HCC.
Liu X, Qi D, Qi J, et al.Significance of DEK overexpression for the prognostic evaluation of non-small cell lung carcinoma.
Oncol Rep. 2016; 35(1):155-62 [PubMed
] Related Publications
In the present study, we explored the role of DEK expression for the prognostic evaluation of non-small cell lung carcinoma (NSCLC). DEK protein and mRNA expression levels were detected in NSCLC cells and fresh tissue samples of NSCLC paired with adjacent non-tumor tissues, respectively. NSCLC cases (n=196) meeting strict follow-up criteria were selected for immunohistochemical staining of DEK protein. Correlations between DEK expression and clinicopathological features of the NSCLC cases were evaluated using Chi-square tests. Survival rates were calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient overall survival was analyzed using Cox proportional hazard analysis. Based on the results, the levels of DEK protein and mRNA were significantly upregulated in 6 fresh tissue samples of NSCLC. Immunohistochemical analysis showed that the DEK expression rate was significantly higher in the NSCLC samples compared with either the adjacent non-tumor tissues or normal lung tissues. DEK expression was correlated with poor differentiation and late pathological stage of NSCLC. DEK expression was also correlated with low disease-free survival and overall survival rates. In the early-stage group, disease-free and overall survival rates of patients with DEK expression were significantly lower than those of patients without DEK expression. Further analysis using a Cox proportional hazard regression model revealed that DEK expression emerged as a significant independent hazard factor for the overall survival rate of patients with NSCLC. Consequently, DEK plays an important role in the progression of NSCLC. DEK may potentially be used as an independent biomarker for the prognostic evaluation of NSCLC.
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.
Abe A, Yamamoto Y, Iba S, et al.NUP214-RAC1 and RAC1-COL12A1 Fusion in Complex Variant Translocations Involving Chromosomes 6, 7 and 9 in an Acute Myeloid Leukemia Case with DEK-NUP214.
Cytogenet Genome Res. 2015; 146(4):279-84 [PubMed
] Related Publications
DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5'-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5'- and 3'-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5'-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML.
In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro, 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents.
Sandén C, Gullberg UThe DEK oncoprotein and its emerging roles in gene regulation.
Leukemia. 2015; 29(8):1632-6 [PubMed
] Related Publications
The DEK oncogene is highly expressed in cells from most human tissues and overexpressed in a large and growing number of cancers. It also fuses with the NUP214 gene to form the DEK-NUP214 fusion gene in a subset of acute myeloid leukemia. Originally characterized as a member of this translocation, DEK has since been implicated in epigenetic and transcriptional regulation, but its role in these processes is still elusive and intriguingly complex. Similarly multifaceted is its contribution to cellular transformation, affecting multiple cellular processes such as self-renewal, proliferation, differentiation, senescence and apoptosis. Recently, the roles of the DEK and DEK-NUP214 proteins have been elucidated by global analysis of DNA binding and gene expression, as well as multiple functional studies. This review outlines recent advances in the understanding of the basic functions of the DEK protein and its role in leukemogenesis.
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC.
Martinez-Useros J, Rodriguez-Remirez M, Borrero-Palacios A, et al.DEK is a potential marker for aggressive phenotype and irinotecan-based therapy response in metastatic colorectal cancer.
BMC Cancer. 2014; 14:965 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: DEK is a transcription factor involved in stabilization of heterochromatin and cruciform structures. It plays an important role in development and progression of different types of cancer. This study aims to analyze the role of DEK in metastatic colorectal cancer.
METHODS: Baseline DEK expression was firstly quantified in 9 colorectal cell lines and normal mucosa by WB. SiRNA-mediated DEK inhibition was carried out for transient DEK silencing in DLD1 and SW620 to dissect its role in colorectal cancer aggressiveness. Irinotecan response assays were performed with SN38 over 24 hours and apoptosis was quantified by flow cytometry. Ex-vivo assay was carried out with 3 fresh tumour tissues taken from surgical resection and treated with SN38 for 24 hours. DEK expression was determined by immunohistochemistry in 67 formalin-fixed paraffin-embedded tumour samples from metastatic colorectal cancer patients treated with irinotecan-based therapy as first-line treatment.
RESULTS: The DEK oncogene is overexpressed in all colorectal cancer cell lines. Knock-down of DEK on DLD1 and SW620 cell lines decreased cell migration and increased irinotecan-induced apoptosis. In addition, low DEK expression level predicted irinotecan-based chemotherapy response in metastatic colorectal cancer patients with KRAS wild-type.
CONCLUSIONS: These data suggest DEK overexpression as a crucial event for the emergence of an aggressive phenotype in colorectal cancer and its potential role as biomarker for irinotecan response in those patients with KRAS wild-type status.
Yi HC, Liu YL, You P, et al.Overexpression of DEK gene is correlated with poor prognosis in hepatocellular carcinoma.
Mol Med Rep. 2015; 11(2):1318-23 [PubMed
] Related Publications
The oncogene DEK was originally identified as one of the parts of the DEK‑CAN fusion gene, arising from the translocation (6;9) in a subtype of acute myeloid leukemia. Since then, DEK has been shown to promote tumorigenesis in a variety of cancer cell types through its roles in inhibiting cell differentiation, senescence and apoptosis. Certain studies have established that DEK is dysregulated in several types of cancer, including hepatocellular carcinoma (HCC). However, its clinical significance in human HCC remains unknown. In this study, the expression of DEK mRNA and protein was examined in 55 surgical HCC specimens and matched non‑tumorous tissues. In addition, the correlation between DEK expression and clinicopathological characteristics and prognosis was analyzed. mRNA and protein levels of DEK were found to be significantly overexpressed in the majority of HCC tumors when compared with matched normal hepatic tissues (P<0.05). In addition, the expression pattern of DEK was closely correlated with differentiation status, portal venous invasion and tumor size (P<0.05). Kaplan‑Meier curves demonstrated that patients with higher DEK expression levels had significantly poorer survival than those with lower DEK expression levels (P=0.003). In addition, Cox regression analysis demonstrated that the level of DEK expression may be a valuable prognostic factor (P<0.05). These results suggested that DEK may play a significant role in hepatocyte differentiation and may serve as a useful prognostic marker and biomarker for the staging of HCC.
Our previous study indicated that DEK protein was overexpressed in colorectal carcinoma (CRC) compared with the normal colorectal mucosa. DEK was also significantly correlated with the prognostic characteristics of patients with CRC, demonstrating that DEK played an important role in CRC progression. In this work, we evaluate the effects of DEK on biological behaviors in CRC and explore the related molecular mechanisms. The results showed that DEK was overexpressed in human CRC tissues, and was correlated with the Ki-67 index and the apoptotic index. DEK depletion by RNAi in SW-620 and HCT116 cells significantly decreased cell proliferation, but increased cell apoptosis. Upregulation of DEK was involved in the p53/MDM, Bcl-2 family, and caspase pathways. Our study demonstrates that DEK promotes the growth of CRC, and could be a therapeutic target in CRC.
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, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.
There are two major pathways leading to induction of NF-κB subunits. The classical (or canonical) pathway typically leads to the induction of RelA or c-Rel containing complexes, and involves the degradation of IκBα in a manner dependent on IκB kinase (IKK) β and the IKK regulatory subunit NEMO. The alternative (or non-canonical) pathway, involves the inducible processing of p100 to p52, leading to the induction of NF-κB2(p52)/RelB containing complexes, and is dependent on IKKα and NF-κB inducing kinase (NIK). Here we demonstrate that in primary human fibroblasts, the alternative NF-κB pathway subunits NF-κB2 and RelB have multiple, but distinct, effects on the expression of key regulators of the cell cycle, reactive oxygen species (ROS) generation and protein stability. Specifically, following siRNA knockdown, quantitative PCR, western blot analyses and chromatin immunoprecipitation (ChIP) show that NF-κB2 regulates the expression of CDK4 and CDK6, while RelB, through the regulation of genes such as PSMA5 and ANAPC1, regulates the stability of p21WAF1 and the tumour suppressor p53. These combine to regulate the activity of the retinoblastoma protein, Rb, leading to induction of polycomb protein EZH2 expression. Moreover, our ChIP analysis demonstrates that EZH2 is also a direct NF-κB target gene. Microarray analysis revealed that in fibroblasts, EZH2 antagonizes a subset of p53 target genes previously associated with the senescent cell phenotype, including DEK and RacGAP1. We show that this pathway provides the major route of crosstalk between the alternative NF-κB pathway and p53, a consequence of which is to suppress cell senescence. Importantly, we find that activation of NF-κB also induces EZH2 expression in CD40L stimulated cells from Chronic Lymphocytic Leukemia patients. We therefore propose that this pathway provides a mechanism through which microenvironment induced NF-κB can inhibit tumor suppressor function and promote tumorigenesis.
Logan GE, Mor-Vaknin N, Braunschweig T, et al.DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML).
Blood Cells Mol Dis. 2015; 54(1):123-31 [PubMed
] Related Publications
DEK is important in regulating cellular processes including proliferation, differentiation and maintenance of stem cell phenotype. The translocation t(6;9) in Acute Myeloid Leukemia (AML), which fuses DEK with NUP214, confers a poor prognosis and a higher risk of relapse. The over-expression of DEK in AML has been reported, but different studies have shown diminished levels in pediatric and promyelocytic leukemias. This study has characterized DEK expression, in silico, using a large multi-center cohort of leukemic and normal control cases. Overall, DEK was under-expressed in AML compared to normal bone marrow (NBM). Studying specific subtypes of AML confirmed either no significant change or a significant reduction in DEK expression compared to NBM. Importantly, the similarity of DEK expression between AML and NBM was confirmed using immunohistochemistry analysis of tissue mircorarrays. In addition, stratification of AML patients based on median DEK expression levels indicated that DEK showed no effect on the overall survival of patients. DEK expression during normal hematopoiesis did reveal a relationship with specific cell types implicating a distinct function during myeloid differentiation. Whilst DEK may play a potential role in hematopoiesis, it remains to be established whether it is important for leukemagenesis, except when involved in the t(6;9) translocation.
PURPOSE: We sought to systematically define determinants of the response to neoadjuvant chemotherapy to elucidate predictive biomarkers for breast cancer.
EXPERIMENTAL DESIGN: An unbiased systematic analysis was performed in multiple independent datasets to define genes predictive of complete pathologic response (pCR) following treatment with neoadjuvant chemotherapy. These genes were interrogated across estrogen receptor (ER)-positive and ER-negative breast cancer and those in common across three different treatment regimens were analyzed for optimal predictive power. Subsequent validation was performed on independent cohorts by gene expression and IHC analyses.
RESULTS: Genes that were highly associated with the response to neoadjuvant chemotherapy in breast cancer were readily defined using a computational method ranking individual genes by their respective ROC. Such predictive genes of the response to taxane-associated therapies were strongly enriched for cell-cycle control processes in both ER-positive and ER-negative breast cancer and correlated with pCR. However, other genes that were specifically associated with residual disease were also identified under other treatment conditions. Using the intersection between treatment groups, nine genes were identified that harbored strong predictive power in multiple contexts and validation cohort. In particular, the nuclear oncogene DEK was strongly associated with pCR, whereas the cell surface protein BCAM was strongly associated with residual disease. By IHC staining, these markers exhibited potent predictive power that remained significant in multivariate analysis.
CONCLUSION: Systematic computational approaches can define key genes that will be able to predict the response to chemotherapy across multiple treatment modalities yielding a small collection of biomarkers that can be readily deployed by IHC analyses.
Disease progression and recurrence are major barriers to survival for breast cancer patients. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly overexpressed breast cancer oncogenes, Ron (Recepteur d'Origine Nantaise) and DEK, cooperate to promote advanced disease through multipronged effects on β-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron overexpression in human disease stimulates β-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including β-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis and fewer cells expressing mammary cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical β-catenin signaling loop. Finally, we show that Dek overexpression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK overexpression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/β-catenin signaling.
Takeda A, Yaseen NRNucleoporins and nucleocytoplasmic transport in hematologic malignancies.
Semin Cancer Biol. 2014; 27:3-10 [PubMed
] Related Publications
Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins. Rearrangements of the genes encoding two nucleoporins, NUP98 and NUP214, have been implicated in the pathogenesis of several types of hematologic malignancies, particularly acute myeloid leukemia. NUP98 rearrangements result in fusion of an N-terminal portion of NUP98 to one of numerous proteins. These rearrangements often follow treatment with topoisomerase II inhibitors and tend to occur in younger patients. They have been shown to induce leukemia in mice and to enhance proliferation and disrupt differentiation in primary human hematopoietic precursors. NUP214 has only a few fusion partners. DEK-NUP214 is the most common NUP214 fusion in AML; it tends to occur in younger patients and is usually associated with FLT3 internal tandem duplications. The leukemogenic activity of NUP214 fusions is less well characterized. Normal nucleoporins, including NUP98 and NUP214, have important functions in nucleocytoplasmic transport, transcription, and mitosis. These functions and their disruptions by oncogenic nucleoporin fusions are discussed.
Yu T, Lu Q, Ou X, et al.Association of sedentary behavior with the expression levels of biomarkers in colorectal cancer: clinical analysis of 228 patients.
Tohoku J Exp Med. 2014; 232(3):167-76 [PubMed
] Related Publications
There is an association between sedentary behavior and the risk of colorectal cancer (CRC), but the underlying mechanism is unclear. CRC is characterized by the changes in the expression levels of biomarkers, including voltage-gated proton channel Hv1, matrix-remodeling associated 5 (MXRA5), DEK (inducing positive supercoils into circular DNA) and protein inhibitor of activated signal transducer and activators of transcription 3 (PIAS3). Thus, sedentary behavior may affect the expression levels of these biomarkers in the colorectal tissue. Here, we recruited 228 CRC patients (128 males, 57.8 ± 7.8 years; 100 females, 57.7 ± 7.5 years) and 80 healthy subjects (48 males, 57.5 ± 6.8 years; 32 females, 56.9 ± 6.5 years) from March 7th, 2010 to May 6th, 2012. All the subjects were unrelated Han Chinese with the similar cultural and economic background. All the subjects were interviewed concerning sedentary time (sitting time categories: less than 1, 1-3, 4-6, and more than 6 h/day). The daily sedentary time of most CRC patients was more than 4 h/day, while the sedentary time of most healthy subjects was less than 3 h/day. The expression levels of Hv1, MXRA5 and DEK mRNAs and proteins were higher in CRC tissues and the levels of PIAS3 mRNA and protein were lower when the daily sedentary time was longer in CRC patients (p < 0.05). The daily sedentary time was correlated with the protein levels of CRC biomarkers. Furthermore, the sedentary time was positively related with body mass index but not daily calorie intake.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and patient outcomes using current treatments remain poor. Tumor development is etiologically associated with tobacco or alcohol use and/or human papillomavirus (HPV) infection. HPV-positive HNSCCs, which frequently harbor wild-type p53, carry a more favorable prognosis and are a biologically distinct subgroup when compared with their HPV-negative counterparts. HPV E7 induces expression of the human DEK gene, both in vitro and in vivo. In keratinocytes, DEK overexpression is sufficient for causing oncogenic phenotypes in the absence of E7. Conversely, DEK loss results in cell death in HPV-positive cervical cancer cells at least in part through p53 activation, and Dek knockout mice are relatively resistant to the development of chemically induced skin papillomas. Despite the established oncogenic role of DEK in HPV-associated cervical cancer cell lines and keratinocytes, a functional role of DEK has not yet been explored in HNSCC. Using an established transgenic mouse model of HPV16 E7-induced HNSCC, we demonstrate that Dek is required for optimal proliferation of E7-transgenic epidermal cells and for the growth of HNSCC tumors. Importantly, these studies also demonstrate that DEK protein is universally upregulated in both HPV-positive and -negative human HNSCC tumors relative to adjacent normal tissue. Furthermore, DEK knockdown inhibited the proliferation of HPV-positive and -negative HNSCC cells, establishing a functional role for DEK in human disease. Mechanistic studies reveal that attenuated HNSCC cell growth in response to DEK loss was associated with reduced expression of the oncogenic p53 family member, ΔNp63. Exogenous ΔNp63 expression rescued the proliferative defect in the absence of DEK, thereby establishing a functional DEK-ΔNp63 oncogenic pathway that promotes HNSCC. Taken together, our data demonstrate that DEK stimulates HNSCC cellular growth and identify ΔNp63 as a novel DEK effector.
Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.
Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.
BACKGROUND: The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions.
METHODS: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions.
RESULTS: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation was determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A global translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift from glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a concomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1 activity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced proliferation, demonstrating that the effect is mTOR-dependent.
CONCLUSIONS: Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of mTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with mTOR inhibitors.
BACKGROUND: The DEK protein is related to chromatin reconstruction and gene transcription, and plays an important role in cell apoptosis. High expression levels of the human DEK gene have been correlated with numerous human malignancies. This study explores the roles of DEK in tumor progression and as a prognostic determinant of colorectal cancer.
METHODS: Colorectal cancer specimens from 109 patients with strict follow-up, and colorectal adenomas from 52 patients were selected for analysis of DEK protein by immunohistochemistry. The correlations between DEK over expression and the clinicopathological features of colorectal cancers were evaluated by Chi-square test and Fisher's exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models.
RESULTS: DEK protein showed a nuclear immunohistochemical staining pattern in colorectal cancers. The strongly positive rate of DEK protein was 48.62% (53/109) in colorectal cancers, which was significantly higher than that in either adjacent normal colon mucosa (9.17%, 10/109) or colorectal adenomas (13.46%, 7/52). DEK over expression in colorectal cancers was positively correlated with tumor size, grade, lymph node metastasis, serosal invasion, late stage, and disease-free survival- and 5-year survival rates. Further analysis showed that patients with late stage colorectal cancer and high DEK expression had worse survival rates than those with low DEK expression. Moreover, multivariate analysis showed high DEK expression, serosal invasion, and late stage are significant independent risk factors for mortality in colorectal cancer.
CONCLUSIONS: DEK plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor of colorectal cancers.
Shiba N, Ichikawa H, Taki T, et al.NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia.
Genes Chromosomes Cancer. 2013; 52(7):683-93 [PubMed
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The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.
The human DEK proto-oncogene is a nuclear protein with suspected roles in human carcinogenesis. DEK appears to function in several nuclear processes, including transcriptional regulation and modulation of chromatin structure. To investigate the clinicopathological significance of DEK in patients with non-small cell lung cancer (NSCLC), we analyzed DEK immunohistochemistry in 112 NSCLC cases. The results showed that DEK was overexpressed mainly in the nuclear compartment of tumor cells. In squamous cell carcinoma, DEK-positive expression occurred in 47.9% (23/48) of cases, and in lung adenocarcinoma, DEK-positive expression occurred in 67.2% (43/64) of cases and correlated with differentiation, p-TNM stage, and nodal status. Moreover, in lung adenocarcinoma, DEK expression was significantly higher compared with DEK expression in squamous cell carcinoma. Kaplan-Meier analysis showed that patients with low DEK expression had higher overall survival compared with patients with high DEK expression. Depleting DEK expression inhibited cellular proliferation and migration. Furthermore, in DEK-depleted NSCLC cells, we found that RhoA expression was markedly reduced; in conjunction, active RhoA-GTP levels and the downstream effector phosphorylated MLC2 were also reduced. Taken together, DEK depletion inhibited cellular migration in lung cancer cell lines possibly through inactivation of the RhoA/ROCK/MLC signal transduction pathway.
Expression of estrogen and progesterone hormone receptors indicates a favorable prognosis due to the successful use of hormonal therapies such as tamoxifen and aromatase inhibitors. Unfortunately, 15-20% of patients will experience breast cancer recurrence despite continued use of tamoxifen. Drug resistance to hormonal therapies is of great clinical concern so it is imperative to identify novel molecular factors that contribute to tumorigenesis in hormone receptor positive cancers and/or mediate drug sensitivity. The hope is that targeted therapies, in combination with hormonal therapies, will improve survival and prevent recurrence. We have previously shown that the DEK oncogene, which is a chromatin remodeling protein, supports breast cancer cell proliferation, invasion and the maintenance of the breast cancer stem cell population. In this report, we demonstrate that DEK expression is associated with positive hormone receptor status in primary breast cancers and is up-regulated in vitro following exposure to the hormones estrogen, progesterone, and androgen. Chromatin immunoprecipitation experiments identify DEK as a novel estrogen receptor α (ERα) target gene whose expression promotes estrogen-induced proliferation. Finally, we report for the first time that DEK depletion enhances tamoxifen-induced cell death in ER+ breast cancer cell lines. Together, our data suggest that DEK promotes the pathogenesis of ER+ breast cancer and that the targeted inhibition of DEK may enhance the efficacy of conventional hormone therapies.
Human oncogene DEK has been shown to be upregulated in a number of neoplasms. The purpose of this study was to investigate DEK expression level in chronic lymphocytic leukemia (CLL), analyze the correlation between DEK expression and CLL prognostic markers, and characterize the role of DEK in the response to either chemotherapeutic drugs or nongenotoxic activators of the p53 pathway. DEK mRNA was evaluated by real-time quantitative reverse transcriptase-polymerase chain reaction (qPCR), and primary CLL samples were treated in vitro with either fludarabine or Nutlin-3 to explore the interaction of p53 status and DEK mRNA expression. The median expression levels of DEK mRNA were 6.792 × 10 (-2) (1.438 × 10 (-2) -3.201 × 10 (-1) ) in 65 patients with CLL. A marked increase of DEK mRNA expression was observed in the CLL patients with unmutated immunoglobulin heavy chain variable (IGHV) gene (p = 0.025), CD38-positive (p = 0.047), del(17p13) (p = 0.006). Both fludarabine and Nutlin-3 significantly downregulated DEK in the primary CLL cells which were with normal function of p53, or without deletion or mutation of p53 (p = 0.042, p = 0.038; p = 0.021, p = 0.017; p = 0.037, p = 0.017). However, the downregulation of DEK was not observed in the primary CLL cells which were with dysfunction of p53, or with deletion or mutation of p53 (p = 0.834, p = 0.477; p = 0.111, p = 0.378; p = 0.263, p = 0.378). These data show that DEK might be applied for the assessment of prognosis in patients with CLL, and fludarabine and Nutlin-3 regulate DEK expression depended on p53 status.
Geng Z, Zhang H, Wang D, et al.Combination of cytogenetic analysis and molecular screening in patients with de novo acute myeloid leukemia.
J Huazhong Univ Sci Technolog Med Sci. 2012; 32(4):501-10 [PubMed
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Nowadays the role of genetic findings in determining the diagnosis, therapy and prognosis of acute myeloid leukemia (AML) has become more valuable. To improve and validate the detection of clonal chromosomal aberrations in leukemia, we designed a combined application of karyotyping with multiplex reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), and addressed the expression and distribution of fusion genes among the subtypes of Chinese adult patients with de novo AML. Multiplex RT-PCR assays were performed on 477 samples from newly diagnosed AML patients, and cytogenetic data were obtained from 373 of them by R or G banding techniques and those in some cases were confirmed by FISH. The PCR products in some suspected cases were tested by two-directional sequencing. The results showed that except unqualified samples, fusion genes were detected by multiplex RT-PCR in 211 of 474 patients (44.51%), including AML1-ETO, CBFβ-MYH11, PML-RARα, PLZF-RARα, NPM-RARα, MLL rearrangements, BCR-ABL, DEK-CAN, SET-CAN, TEL-PDGFR, TLS-ERG, AML1-MDS1 (EVI-1). In 373 patients, who took both multiplex RT-PCR and karyotype analysis, the detection rate of chromosomal aberrations by using multiplex RT-PCR and karyotyping was 160/373 (42.89%) and 179/373 (47.98%) respectively, and the combination could optimize the detection rate of clonal genetic abnormalities to 216/373 (57.90%). The PCR results from 11 cases "normal" in karyotyping but abnormal in RT-PCR for MLL rearrangements were confirmed by two-directional sequencing. It is concluded that karyotype studies remain the cornerstone for genetic testing; conventional cytogenetics and molecular-based methods are complementary tests for the detection of clonal genetic aberrations in AML, especially for the cryptic or submicroscopic aberrations. Once a genetic marker has been identified by combined analysis, it could be used to monitor residual disease during/after chemotherapy, by quantitative RT-PCR and/or FISH.
Head and neck cancer is a devastating disease that afflicts many individuals worldwide. Conventional therapies are successful in only a limited subgroup and often leave the patient with disfigurement and long lasting adverse effects on normal physiologic functions. The field is in dire need of new therapies. Oncolytic viral as well as targeted therapies have shown some success in other malignancies and are attractive for the treatment of head and neck cancer. Recently, it has been shown that a subset of head and neck cancers is human papillomavirus (HPV) positive and that this subset of cancers is biologically distinct and more sensitive to chemoradiation therapies although the underlying mechanism is unclear. However, chemoresistance remains a general problem. One candidate mediator of therapeutic response, which is of interest for the targeting of both HPV-positive and -negative tumors is the human DEK proto-oncogene. DEK is upregulated in numerous tumors including head and neck cancers regardless of their HPV status. Depletion of DEK in tumor cells in culture results in sensitivity to genotoxic agents, particularly in rapidly proliferating cells. This suggests that tumors with high DEK protein expression may be correlated with poor clinical response to clastogenic therapies. Targeting molecules such as DEK in combination with new and/or conventional therapies, holds promise for novel future therapeutics for head and neck cancer.