Death-associated Protein Kinase Promoter Research Articles

Mechanism of cAMP Response Element-binding Protein 1/Death-associated Protein Kinase 1 Axis-mediated Hippocampal Neuron Apoptosis in Rat Brain Injury After Cardiopulmonary Resuscitation

Brain injury represents a leading cause of deaths following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). This study explores the role of CREB1 (cAMP responsive element binding protein 1)/DAPK1 (death associated protein kinase 1) axis in brain injury after CPR. CA was induced by asphyxia in rats, followed by CPR. After CREB1 over-expression, the survival rate and neurological function score of rats were measured. Nissl and TUNEL staining evaluated the pathological condition of hippocampus and apoptosis of hippocampal neurons respectively. H19-7 cells were subjected to OGD/R and infected with oe-CREB1. CCK-8 assay and flow cytometry measured the cell viability and apoptosis. CREB1, DAPK1, and cleaved Caspase-3 expressions were examined using Western blot. The binding between CREB1 and DAPK1 was determined using ChIP and dual-luciferase reporter assays. CREB1 was poorly expressed while DAPK1 was highly expressed in rat hippocampus after CPR. CREB1 overexpression improved rat neurological function, repressed neuron apoptosis, and reduced cleaved Caspase-3 expression. CREB1 was enriched on the DAPK1 promoter and suppressed DAPK1 expression. DAPK1 overexpression reversed the inhibition of OGD/R-insulted apoptosis by CREB1 overexpression. To conclude, CREB1 suppresses hippocampal neuron apoptosis and mitigates brain injury after CPR by inhibiting DAPK1 expression.

Clinicopathological significance of DAPK gene promoter hypermethylation in non-small cell lung cancer: A meta-analysis.

Death-associated protein kinase (DAPK) has a strong function of tumor suppression involving apoptosis regulation, autophagy, and metastasis inhibition. Hypermethylation of CpG islands in DAPK gene promoter region is one of the important ways to inactivate this tumor suppressor gene, which might promote lung carcinogenesis. However, the clinicopathological significance of the DAPK promoter hypermethylation in lung cancer remains unclear. In this study, we performed a meta-analysis trying to estimate the clinicopathological significance of DAPK promoter hypermethylation in non-small cell lung cancer (NSCLC). A detailed literature search for publications relevant to DAPK gene promoter methylation and NSCLC was made in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, CSTJ, Wanfang databases, and SinoMed (CBM). The random-effects model and fixed-effects model were utilized to pool the relative ratio based on the heterogeneity test in the meta-analysis. A total of 41 studies with 3348 patients were included. The frequency of DAPK methylation was significantly higher in NSCLC than in non-malignant control (odds ratio (OR) = 6.88, 95% confidence interval (CI): 4.17-11.35, P < 0.00001). The pooled results also showed that DAPK gene promoter hypermethylation was significantly associated with poor prognosis for overall survival in patients with NSCLC (hazard ratio: 1.23, 95% CI:1.01-1.52, P = 0.04). Moreover, DAPK gene promoter hypermethylation was significantly associated with squamous cell carcinoma (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04) and smoking behavior (OR: 1.42, 95% CI: 1.04-1.93, P = 0.03) but not with TNM stage, tumor differentiation, age, or gender. DAPK promoter hypermethylation might be a candidate diagnostic and prognostic tumor marker for NSCLC.

Comparative study of death-associated protein kinase promoter methylation between nonsquamous and squamous subtypes of nonsmall cell lung cancer

Background Lung cancer is a leading cause of cancer-related mortality in the world. Nonsmall cell lung cancer (NSCLC) can be classified as nonsquamous cell carcinoma (non-SCC) and squamous cell carcinoma (SCC). NSCLC pathogenesis includes altered methylation patterns in multiple genes. Promotor methylation of death-associated protein kinase (DAPK) has been documented in various tumors. Aim To compare DAPK promoter methylation and clinical characteristics in patients of nonsquamous cell lung cancer with those of SCC. Patients and methods A case–control study was conducted on fresh-frozen tumor samples from 81 patients with primary NSCLC, including 43 non-SCC cases and 38 SCC cases, investigated in the Chest Department, Mansoura University Hospital, in the period from June 2017 to January 2020. A total of 40 patients matched for age and sex with nonmalignant lung lesions served as controls. Patients with age more than 18 years, radiological suggestions of lung cancer, and histologically diagnosed NSCLC were included, whereas patients with malignancies other than NSCLC or unfit for bronchoscopy were excluded. A pathologist histologically examined each lung tumor to define the type and other clinical characteristics of the tumor. DNA was isolated from fresh-frozen tissues, and the detection of DNA methylation was performed using methylation-specific PCR. Results NSCLC case groups included 43 nonsquamous cells and 38 squamous cells, with a mean age of 62.89±5.5 and 64.19±5.87 years, respectively. The control group included 40 patients, with a mean age of 61.37±6.64 years. There were statistically significant differences regarding smoking status (P=0.002) and the clinical characteristics suggestive of lung cancer between both patients with NSCLC and controls, but the differences between SCC and non-SCC were not significant. The results were significantly different between the two groups concerning chest radiograph and computed tomographic finding, where the peripheral mass was significantly higher in non-SCC than SCC (P&lt;0.001). DAPK promoter methylation was significantly higher for NSCLC (both SCC and non-SCC) as compared with controls (P≤0.001), but there was no significant difference between SCC and non-SCC groups. Conclusion Detection of the aberrant DAPK hypermethylation in tumor DNA from patients with NSCLC may provide an effective means for early auxiliary diagnosis of the malignancy but cannot distinguish between the histopathological types.

Meta-analysis: Assocation between promoter hypermethylation of DAPK (Death-Associated Protein Kinase) and cervical cancer

Purpose: Death-associated protein kinase (DAPK or DAPK1) is an important tumor suppressor protein that involved in the regulation of cell activities. The aberrant methylation of DAPK promoter has been reported in patients with cervical cancer. However, the association between of DAPK1 and cervical cancer was not always unification, in previous studies. Therefore, in current study, a meta-analysis was performed for association of between DAPK gene’s promoter hypermethylated and cervical cancer.&#x0D; Methods: A systematic literature analysis was conducted based on the previous studies published in PubMed, PubMed Central (NCBI), Google by using following keywords: cervical cancer, cervical carcinoma, Methylation, by the end of January, 2018. The association between DAPK promoter methylation and cervical cancer was evaluated by odds ratio (ORs) and 95% confidence intervals (CI). To evaluate the potential sources of heterogeneity, the meta-regression analysis and subgroup analysis were conducted.&#x0D; Results: A total of 21 case-control studies which relevant to the association between DAPK1 gene’s promoter methylation frequency and cervical cancer, that including 1600 cancer cases and 1011 control cases (non-cancerous cases). The analysis results indicated that the characteristic of candidate gene’s promoter methylation increased the cervical cancer risk through the calculation of OR value (OR = 21.25; 95% CI = 8.73 – 52.97; p &lt; 0.001; Random effect model). The association between DAPK1 gene’s promoter hypermethylation was confirmed in all the subgroups analyses, including materials and assays methods, ethnicity. Furthermore, this association is higher in cervical squamous cell carcinoma than cervical adenocarcinoma and is a characteristic of late-stage disease.&#x0D; Conclusion: The hypermethylated DAPK1 gene’s promoter was also one of etiological factor, lead to the cervical tumorigenesis.

Promoter methylation of tumor suppressor genes induced by human papillomavirus in cervical cancer.

Cervical cancer is the most fourth common cancer in women worldwide. The E6 and E7 high-risk human papillomavirus (HPV) types are the main cause of this cancer. Several studies have revealed that promoter methylation of tumor suppressor genes is induced by HPV E7. Recently, it was found that HPV16-E7 and the DNA methyltransferase 1 complex could bind at the cyclin A1 (CCNA1) promoter, resulting in CCNA1 promoter methylation. Therefore, there is a need to study other tumor suppressor genes for which HPV may induce promoter methylation. The present study investigated whether HPV induced cell adhesion molecule 1 (CADM1) and death associated protein kinase 1 (DAPK1) promoter methylation. C33a (no HPV infection) and SiHa (HPV 16 infection) cell lines were used for methylation status and expression observation. It was found that CADM1 and DAPK1 promoter methylation, no expression of CADM1 and decreased expression of DAPK1, was presented in SiHa cells. While no promoter methylation of these two genes was observed in C33a cells, with positive expression of the genes. It was subsequently investigated whether E6 and/or E7 could induce promoter methylation and decrease the expression of these two genes. Methylation-specific primer PCR and quantitative PCR were performed to elucidate the promoter methylation status and expression of CADM1 and DAPK1 in C33a cells transfected with HPV16 E6-PCDNA3 or HPV16 E7-PCDNA3.1 myc-his, compared to empty vector-transfected cells. The results showed that HPV E7 could induce CADM1 promoter methylation and decrease the gene expression in HPV E7 transfected C33a cells, while HPV E6 could induce DAPK1 promoter methylation and decrease its expression in C33a cells transfected with HPV E6. Finally, the mechanism by which HPV E7 induced CADM1 promoter methylation was observed by performing chromatin immunoprecipitation; the data showed that E7 induced CADM1 methylation by the same mechanism as that for CCNA1, by binding at the CADM1 promoter, resulting in the subsequent reduction of its expression in cervical cancer.

Association of Protein Expression and Methylation of DAPK1 with Clinicopathological Features in Invasive Ductal Carcinoma Patients from Kashmir

Aims:Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic Ser/Thr kinase that participates in cell apoptosis and tumor suppression. DAPK1 is frequently lost in many different tumor types including breast cancer. The aim of this study was to evaluate the promoter methylation status of DAPK1 and a possible correlation with the expression of DAPK1 and standard clinicopathological features in invasive ductal breast carcinoma patients (IDC).Methods:Methylation Specific PCR (MSP) was carried out to investigate the promoter methylation status of DAPK1 from 128 breast cancer patients. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry (n=128) and western blotting (n=56).Results:We found significant difference in DAPK1 promoter methylation frequency among breast tumors when compared with the corresponding normal tissues. Hypermethylation of DAPK1 is significantly correlated with the loss of DAPK1 protein expression (P < .001, rs= -0.361). The loss of DAPK1 protein was significantly associated with estrogen receptor (ER) negativity (p= 0.003), triple negative breast cancer (TNB) (p= 0.024) and advanced tumor stages (P = 0.001). Moreover, age at diagnosis (p= 0.041), tumor stage (p= 0.034), ER negativity (p= 0.004) and TNB cancers (p=0.003) correlated significantly with the hypermethylation of the DAPK1 promoter.Coclusion:This study indicates that DAPK1 is methylated in IDC and promoter hypermethylation could be attributed to silencing of DAPK1 gene expression in breast cancer. Thus, we consider DAPK1 inactivation by promoter hypermethylation likely plays a role in the development and progression of breast cancer.

Prognostic significance of DAPK promoter methylation in lymphoma: A meta-analysis.

We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma.

Clinicopathological significance of DAPK promoter methylation in non-small-cell lung cancer: a systematic review and meta-analysis.

BackgroundLung carcinogenesis is related to silencing of tumor suppressor genes and activation of oncogenes. The aim was to investigate the significance of death-associated protein kinase (DAPK) methylation in non-small-cell lung cancer (NSCLC) through a meta-analysis.MethodsA detailed literature search was made in PubMed, Embase, and Web of Science databases. All analysis was performed with Review Manager 5.2.ResultsIn total, 28 studies with a total of 2,148 patients were involved. The frequency of DAPK promoter hypermethylation was 40.50% in NSCLC, significantly higher than in nonmalignant lung tissue; the pooled OR was 5.69, P<0.00001. Additionally, DAPK promoter hypermethylation was significantly correlated with poor overall survival in patients with NSCLC. However, there was no significant difference found while comparing the rate of DAPK promoter hypermethylation in adenocarcinoma and squamous cell cancer. The rate of DAPK promoter hypermethylation was similar between stage III/IV and stage I/II. In addition, the data showed that DAPK promoter hypermethylation was not associated with smoking behavior in patients with NSCLC.ConclusionDAPK promoter hypermethylation is correlated with risk of NSCLC and is a potential biomarker for prediction of poor prognosis in patients with NSCLC.

Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets.

Background: Promoter hypermethylation in death-associated protein kinase 1 (DAPK1) gene has been long linked to cervical neoplasia, but the established results remained controversial. Here, we performed a meta-analysis to assess the associations of DAPK1 promoter hypermethylation with low-grade intra-epithelial lesion (HSIL), high-grade intra-epithelial lesion (HSIL), cervical cancer (CC), and clinicopathological features of CC.Methods: Published studies with qualitative methylation data were initially searched from PubMed, Web of Science, EMBASE, and China National Knowledge Infrastructure databases (up to March 2018). Then, quantitative methylation datasets, retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, were pooled to validate the results of published studies.Results: In a meta-analysis of 37 published studies, DAPK1 promoter hypermethylation progressively increased the risk of LSIL by 2.41-fold (P = 0.012), HSIL by 7.62-fold (P < 0.001), and CC by 23.17-fold (P < 0.001). Summary receiver operating characteristic curves suggested a potential diagnostic value of DAPK1 promoter hypermethylation in CC, with a large area-under-the-curve of 0.83, a high specificity of 97%, and a moderate sensitivity of 59%. There were significant impacts of DAPK1 promoter hypermethylation on histological type (odds ratio (OR) = 3.53, P < 0.001) and FIGO stage of CC (OR = 2.15, P = 0.003). Then, a pooled analysis of nine TCGA and GEO datasets, covering 13 CPG sites within DAPK1 promoter, identified eight CC-associated sites, six sites with diagnostic values for CC (pooled specificities: 74–90%; pooled sensitivities: 70–81%), nine loci associated with the histological type of CC, and all 13 loci with down-regulated effects on DAPK1 mRNA expression.Conclusion: The meta-analysis suggests that DAPK1 promoter hypermethylation is significantly associated with the disease severity of cervical neoplasia. DAPK1 methylation detection exhibits a promising ability to discriminate CC from cancer-free controls.

The prognostic value of DAPK1 hypermethylation in gliomas: A site-specific analysis

Background and aimsThe gene of death associated protein kinase 1 (DAPK1) has been reported to be methylated in various cancers including gliomas. However, its prognostic value for gliomas is still controversy, and the methylation at specific CpG sites of DAPK1 has not been investigated. The aim of this study was to prognostically evaluate the methylation level of different CpG sites within DAPK1 promoter region in gliomas. MethodsBased on sodium bisulfite treated DNA products, we made use of DNA pyrosequencing method to evaluate overall and site-specific methylation of DAPK1 in 143 gliomas and 26 benign tumors (meningeomas) or normal brain tissues. We both statistically analyzed the association between methylation levels of each CpG site and the clinicopathological characteristics, and estimated the prognosis predictive value of site-specific methylation for glioma patients. ResultsMethylation status of DAPK1 site −1527, −1543, and the overall five sites concerned was higher in gliomas than controlled subjects (p < 0.001). Hypermethylation at site −1527 or together with site −1543 associated with better survival in patients taken postoperative therapies (−1527: p = 0.002; −1527 & −1543: p = 0.023), as well as in patients just underwent radiotherapy after surgery (-1527: p = 0.015; −1527 & −1543: p = 0.030). However, Cox regression analysis indicated the site-specific methylation was not independent contributor for gliomas prognosis. ConclusionAnalysis of DAPK1 gene promoter by quantitative pyrosequencing provided more detailed information of methylation status of CpG sites. DAPK1 methylation level is associated with gliomas clinical features and outcomes. Interestingly, the hypermethylation at site −1527 or together with site −1543 indicated good sensitivity of postoperative therapies, especially radiotherapy. Thus, site specifically analysis of DAPK1 methylation may be a valuable diagnostic and prognostic estimation for gliomas.

Relationship between DAPK methylation and gene inactivation in papillary thyroid carcinoma

To investigate the relationship between the methylation of death-associated protein kinase (DAPK) promoter and gene inactivation in papillary thyroid carcinoma, the technique of methylation-specific polymerase chain reaction (PCR (MSP)) was applied to detect the methylation status of DAPK gene promoter in 70 cases of papillary thyroid carcinoma (study group) and in 50 cases of corresponding adjacent tissues (control group). Immunohistochemical method was used to detect the protein expression; besides, the relationship of DAPK methylation and gene inactivation with pathological factors of papillary thyroid cancer was analyzed. The methylation rate of DAPK was 16% (8/50) in the control group and 71.4% (50/70) in the study group with the difference being statistically significant (χ2 = 19.724, P &lt; 0.01). The methylation of DAPK gene promoter was not associated with age, sex, tumor size, TNM stage, and thyroid capsular infiltration in the study group with papillary thyroid carcinoma ( P &gt; 0.05), but was associated with lymph node metastasis ( P &lt; 0.05). Spearman’s rank correlation analysis showed that the methylation of DAPK promoter was negatively correlated with the expression of DAPK (r = −0.793, P &lt; 0.01). The methylation of CpG island in the promoter region of DAPK gene can lead to gene inactivation and may be involved in the occurrence of papillary thyroid carcinoma.

Death-associated protein kinase promoter methylation correlates with clinicopathological and prognostic features in nonsmall cell lung cancer patients: A cohort study.

The objective was to study the correlation between death-associated protein kinase (DAPK) promoter methylation and the clinicopathological and prognostic features in nonsmall cell lung cancer (NSCLC) patients. A total of 117 NSCLC patients were recruited into our study between December 2012 and December 2014. Methylation-specific polymerase chain reaction was employed to detect the methylation status of DAPK in cancer tissues, peficancerous tissues, and serum samples of 117 NSCLC patients. In addition, serum samples of 115 healthy subjects were analyzed as controls. A literature search of English and Chinese databases, based on predefined criteria, identified published studies closely related to this study. Data were extracted, and meta-analysis was performed using STATA 12.0 software (STATA Corporation, College Station, TX, USA). Our study results showed that DAPK promoter methylation frequency was significantly higher in NSCLC tissues compared to peficancerous normal tissues (58.1% vs. 12.8%, χ2 = 52.45, P < 0.001). When serum samples were compared, DAPK methylation frequency in NSCLC patients was higher than the control group (27.4% vs. 0, χ2 = 37.07, P < 0.001). Our meta-analysis results demonstrated that DAPK methylation frequency was lower in tumor node metastasis (TNM) stage I-II compared to TNM stage III-IV (relative risk [RR] =0.87, 95% confidence interval [CI] =0.76-0.99, P = 0.041). DAPK promoter methylation frequency in NSCLC patients with lymph node metastasis was significantly higher compared to the patients with no metastases (RR = 1.26, 95% CI = 1.04-1.52, P = 0.020). Finally, the 5-year survival rate was lower in NSCLC patient group with high frequency of DAPK methylation, compared to the patient group with unmethylated DAPK (RR = 0.71, 95% CI = 0.56-0.89, P = 0.004). Our results showed that DAPK promoter methylation is tightly correlated with clinicopathological features of NSCLC and is associated with poor prognosis in patients.

IDENTIFICATION OF FREQUENT PROMOTER METHYLATION OF DEATH-ASSOCIATED PROTEIN KINASE IN LIQUID-BASED PAPANICOLAOUS TEST SAMPLES IN VIETNAMESE POPULATION

Objective: The infection of high-risk human papillomavirus (HPV) genotypes, particularly HPV-16 and HPV-18, is known to cause cervical cancer (CC); however, aberrant DNA methylation of death-associated protein kinase (DAPK), a member of tumor suppressor gene family, are required for cervical tumorigenesis. The aim of our study was to evaluate the hypermethylation frequency of CpG belonged to DAPK promoter, in Vietnamese patients, as well as to study about the association between hypermethylation, and high-risk HPV infection leading to CC.Methods: Methylation-specific-polymerase chain reaction (MSP) was performed to analyze methylation status from 109 liquid-based papanicolaous test samples, collected from local hospital and were identified whether HPV/or non-HPV, high-risk/low-risk HPV infection, then was confirmed by sequencing.Results: In the case of high-risk HPV infection, the frequency of DAPK gene hypermethylation was 66.67% (24 of 36 cases). Meanwhile, low hypermethylation status was found in low-risk and non-HPV infection, counting for 12.0% (3 of 25 cases), 2.1% (1 of 48 cases), respectively. Significant association of DAPK hypermethylation with high-risk, low-risk, and non-HPV infection was observed (p&lt;0.0001). The DAPK hypermethylation increased the possibility to CC in the case of high-risk HPV infected with high incidence: Odds ratio=34.5 (95% confidence interval [CI]=10.15-117.23, p&lt;0.01), relative risk=12.2 (95% CI=4.56-32.42, p&lt;0.01).Conclusion: Based on those data, it suggested that MSP carried out on noninvasive samples will lead to potential method to screening, diagnosis and early diagnosis of cervical carcinoma in Vietnamese population.

Characterization of DAPK1 as a novel transcriptional target of BRMS1

Breast cancer metastasis suppressor 1 (BRMS1) can specifically regulate tumor metastasis in many cancers. Our previous studies have demonstrated that BRMS1 can promote cell apoptosis through regulating osteopontin (OPN) expression in hepatocellular carcinoma (HCC) cells. However, the transcriptional targets of BRMS1 have not been thoroughly studied. In this study, death-associated protein kinase1(DAPK1), a tumor suppressor gene with multiple roles in regulating cell death, was identified as a potential transcriptional target of BRMS1 in the whole genome expression microarray. Quantitative real-time PCR and western blot analysis of HCC cells overexpressing BRMS1 further confirmed the transcriptional regulation relationship between BRMS1 and DAPK1. Moreover, DAPK1 expression was frequently decreased or even lost in HCC tissue samples by comparison with neighboring pathologically normal liver tissue, which was consistent with the decreased BRMS1 expression pattern. To unravel the molecular mechanism of BRMS1 in regulating DAPK1, a series of deletion mutants of DAPK1 promoter was subjected to luciferase assay. The luciferase units of -200 to -80bp region, with two tandem putative NF-κB binding sites, were specifically enhanced by BRMS1 expression. Site-directed mutants of NF-κB binding sites blocked the transcriptional activation effect. In addition, the binding capability of BRMS1 and the putative NF-κB binding sites were demonstrated in the chromatin immunoprecipitation (ChIP) assay. In conclusion, our study characterized DAPK1 as a novel transcriptional target of BRMS1. Transcriptional activation of DAPK1 might be another important mechanism accounting for the metastasis suppressive activity of BRMS1.

Promoter methylation and expression of death-associated protein kinase gene in acute leukemia

To study the clinical implications of death-associated protein kinase (DAPK) promoter methylation and DAPK gene expression in untreated patients with acute leukemia. Methylation-specific PCR and RT-PCR were employed to detect the DAPK gene methylation and mRNA expression in the bone marrow of 60 patients with acute myeloid leukemia (AML), 55 patients with acute lymphocytic leukemia (ALL), and 17 normal subjects. The positivity rate of DAPK methylation was significantly higher in ALL patients (29.1%) than in AML patients group (5%) and normal subjects (0%) (P<0.01). No correlation was found between DAPK gene methylation and the clinical features in ALL patients (P>0.05). DAPK mRNA expression level differed significantly among the 3 groups (P=0.000), and was the highest in normal subjects and the lowest in ALL patients. In ALL patients, the expression level of DAPK mRNA showed a significant inverse correlation with DAPK promoter methylation (P<0.05). The methylation rate of DAPK gene is higher in untreated ALL patients than in AML patients and normal subjects. DAPK gene methylation is not correlated with the clinical features of ALL patients but is probably related with the low gene expression level of DAPK in these patients.

Methylation of p16 and death-associated protein kinase promoter gene regions in the blood serum of patients with non-invasive urinary bladder cancer

Objective To investigate p16 and death-associated protein kinase (DAPK) promoter methylation in the blood serum of patients with non-invasive urinary bladder cancer. Methods p16 and DAPK promoter methylations in blood serum of patients with non-invasive urinary bladder cancer (experimental group, n=25) and healthy volunteers (control group, n=25) were detected by methylation specific polymerease chain reaction (MSP), and their clinical implications were analyzed. Results The methylation rate of p16 in experimental group was 52% (13/25), higher than 24% (6/25) in control group(χ2=4.160, P=0.041); The methylation rate of DAPK in experimental group was 60% (15/25), higher than 32% (8/25) in control group (χ2=3.945, P=0.047). Both of them had statistically significant difference. The methylation rate of p16 and DAPK was not correlated with smoking (χ2=0.187, P=0.665; χ2=0.109, P=0.741), age (χ2=0.000, P=0.991; χ2=0.038, P=0.845), gender (χ2=0.746, P=0.382; χ2=1.288, P=0.256) or the grade of tumor (P=1.000; P=1.000). Conclusion p16 and DAPK promoter methylations are closely related to non-invasive urinary bladder cancer. Key words: Bladder cancer; p16; Death-associated protein kinase; Methylation

Association between promoter methylation of DAPK gene and HNSCC: A meta-analysis.

BackgroundThe death-associated protein kinase (DAPK) is a tumor suppressor gene, which is a mediator of cell death of INF-γ–induced apoptosis. Aberrant methylation of DAPK promoter has been reported in patients with head and neck squamous cell carcinoma (HNSCC). However, the results of these studies are inconsistent. Hence, the present study aimed to evaluate the association between the promoter methylation of DAPK gene and HNSCC.MethodsRelevant studies were systematically searched in PubMed, Web of Science, Ovid, and Embase. The association between DAPK promoter methylation and HNSCC was assessed by odds ratio (ORs) and 95% confidence intervals (CI). To evaluate the potential sources of heterogeneity, we conducted the meta-regression analysis and subgroup analysis.ResultsEighteen studies were finally included in the meta-analysis. The frequency of DAPK promoter methylation in patients with HNSCC was 4.09-fold higher than the non-cancerous controls (OR = 3.96, 95%CI = 2.26–6.95). A significant association between DAPK promoter methylation and HNSCC was found among the Asian region and the Non-Asia region (Asian region, OR = 4.43, 95% CI = 2.29–8.58; Non-Asia region, OR = 3.39, 95% CI = 1.18–9.78). In the control source, the significant association between DAPK promoter methylation and HNSCC was seen among the autologous group and the heterogeneous group (autologous group, OR = 2.71, 95% CI = 1.49–4.93; heterogeneous group, OR = 9.50, 95% CI = 2.98–30.27). DAPK promoter methylation was significantly correlated with alcohol status (OR = 1.85, 95% CI = 1.07–3.21).ConclusionThe results of this meta-analysis suggested that aberrant methylation of DAPK promoter was associated with HNSCC.

Promoter methylation of p16 and DAPK genes in brushing, blood, and tissue samples from patients with nasopharyngeal carcinoma: a systematic meta-analysis

Background: Promoter methylation of tumor suppressor genes (TSGs) p16 and death-associated protein kinase ( DAPK ) has been reported in various carcinomas. However, the correlation between p16 or DAPK promoter methylation and the detection of nasopharyngeal carcinoma (NPC) in different sample types remains unclear. Methods: A systematic literature research was conducted to identify available studies. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated and analyzed. Results: Eleven eligible papers on p16 promoter methylation and seven eligible papers on DAPK promoter methylation were included in this analysis. The pooled OR of p16 and DAPK promoter methylation was significantly higher in samples of NPC tissues than in nontumorous (OR =5.49, P 0.1). Conclusions: Our findings suggested that p16 and DAPK promoter methylation may be associated with the carcinogenesis of NPC. Promoter methylation of p16 or DAPK may become a noninvasive biomarker for NPC detection in blood and brushing samples. DAPK or p16 promoter methylation was not correlated with tumor stage. Conducting additional studies is essential in the future to confirm our results.

JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.

Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-κB and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1.

DAPK Promoter Methylation and Bladder Cancer Risk: A Systematic Review and Meta-Analysis.

BackgroundMethylation of tumor suppressor gene promoter leads to transcription inactivation and is involved in tumorigenesis. Several studies demonstrate a potential association between the Death-Associated Protein Kinase (DAPK) gene promoter methylation and bladder cancer risk, tumor stage and histological grade. Due to inconsistent results of these studies, we performed this meta-analysis to ascertain the association.MethodsStudies were retrieved from the PubMed, Embase, Web of Science and the Cochrane Library databases. Study selection and data extraction were executed by two reviewers independently. Meta-analysis was performed using Stata 13.0 and Review Manager 5.3 software.ResultsA total of 21 articles involving 15 case control and 8 case series studies were included in this meta-analysis. DAPK promoter methylation was associated with bladder cancer risk (OR: 5.81; 95%CI = 3.83–8.82, P<0.00001). The frequency of DAPK promoter methylation was equal in bladder cancer tissue and paired adjacent normal tissue (OR: 0.87; 95%CI = 0.31–2.48, P = 0.794). Furthermore, DAPK promoter methylation was associated with higher histological grade (OR: 1.52; 95%CI = 1.10–2.09, P = 0.011) but not associated with tumor stage (OR: 1.12; 95%CI = 0.67–1.87, P = 0.668).ConclusionsThe result suggests that DAPK promoter methylation is significantly increased in bladder cancer patients compared to normal controls. DAPK promoter methylation could serve as a biomarker for bladder cancer detection and management.