Gene Summary

Gene:DAPK2; death associated protein kinase 2
Aliases: DRP1, DRP-1
Summary:This gene encodes a protein that belongs to the serine/threonine protein kinase family. This protein contains a N-terminal protein kinase domain followed by a conserved calmodulin-binding domain with significant similarity to that of death-associated protein kinase 1 (DAPK1), a positive regulator of programmed cell death. Overexpression of this gene was shown to induce cell apoptosis. It uses multiple polyadenylation sites. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:death-associated protein kinase 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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).

Latest Publications: DAPK2 (cancer-related)

Zhang J, Wang J, Luan T, et al.
Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics.
Oncol Rep. 2019; 41(6):3292-3304 [PubMed] Free Access to Full Article Related Publications
The ubiquitin‑specific protease 9X (USP9X) is a conserved deubiquitinase that has been investigated in several types of human cancer. However, the clinical significance and the biological roles of USP9X in prostate cancer remain unexplored. In the present study, an investigation into the expression and clinical significance of USP9X in prostate cancer revealed that USP9X expression was downregulated in prostate cancer tissues compared with that in healthy tissues. In addition, decreased USP9X expression was associated with a higher Gleason score and local invasion. Depletion of USP9X in prostate cancer LNCaP and PC‑3 cells by small interfering RNA promoted cell invasion and migration. Furthermore, USP9X depletion upregulated matrix metalloproteinase 9 (MMP9) and the phosphorylation of dynamin‑related protein 1 (DRP1). Notably, a significant increase in phosphorylated extracellular signal‑regulated kinase (ERK), an upstream activator of MMP9 and DRP1, was observed. To investigate whether ERK activation was able to increase MMP9 protein levels and induce DRP1 phosphorylation, an ERK inhibitor was used, demonstrating that ERK‑mediated MMP9 production and change in mitochondrial function was critical for the biological function of USP9X in prostate cancer cells. In conclusion, the present study demonstrated that USP9X is downregulated in prostate cancer and functions as an inhibitor of tumor cell invasion, possibly through the regulation of the ERK signaling pathway.

Asiaf A, Ahmad ST, Malik AA, et al.
Association of Protein Expression and Methylation of DAPK1 with Clinicopathological Features in Invasive Ductal Carcinoma Patients from Kashmir
Asian Pac J Cancer Prev. 2019; 20(3):839-848 [PubMed] Related Publications
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.

Dong D, Zhang L, Bai C, et al.
UNC5D, suppressed by promoter hypermethylation, inhibits cell metastasis by activating death-associated protein kinase 1 in prostate cancer.
Cancer Sci. 2019; 110(4):1244-1255 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) death primarily occurs due to metastasis of the cells, but little is known about the underlying molecular mechanisms. This study aimed to evaluate the expression of UNC5D, a newly identified tumor suppressor gene, analyze its epigenetic alterations, and elucidate its functional relevance to PCa metastasis. Meta-analysis of publicly available microarray datasets revealed that UNC5D expression was frequently downregulated in PCa tissues and inversely associated with PCa metastasis. These results were verified in clinical specimens by real-time PCR and immunohistochemistry assays. Through methylation analysis, the downregulated expression of UNC5D in PCa tissues and cell lines was found to be attributable to the hypermethylation of the promoter. A negative correlation was observed between methylation and UNC5D mRNA expression in PCa samples. The ectopic expression of UNC5D in PCa cells effectively reduced their ability to migrate and invade both in vitro and in vivo, and siRNA-mediated knockdown of UNC5D yielded consistent results. UNC5D can recruit and activate death-associated protein kinase 1, which remained to be essential for its metastatic suppressor function. In conclusion, these results suggested that UNC5D as a novel putative metastatic suppressor gene that is commonly down-regulated by hypermethylation in PCa.

Aggarwal S, Gabrovsek L, Langeberg LK, et al.
Depletion of dAKAP1-protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility.
J Biol Chem. 2019; 294(9):3152-3168 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Breast cancer screening and new precision therapies have led to improved patient outcomes. Yet, a positive prognosis is less certain when primary tumors metastasize. Metastasis requires a coordinated program of cellular changes that promote increased survival, migration, and energy consumption. These pathways converge on mitochondrial function, where distinct signaling networks of kinases, phosphatases, and metabolic enzymes regulate these processes. The protein kinase A-anchoring protein dAKAP1 compartmentalizes protein kinase A (PKA) and other signaling enzymes at the outer mitochondrial membrane and thereby controls mitochondrial function and dynamics. Modulation of these processes occurs in part through regulation of dynamin-related protein 1 (Drp1). Here, we report an inverse relationship between the expression of dAKAP1 and mesenchymal markers in breast cancer. Molecular, cellular, and

Strzelczyk JK, Krakowczyk Ł, Owczarek AJ
Methylation status of SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes in patients with oral squamous cell carcinoma.
Arch Oral Biol. 2019; 98:265-272 [PubMed] Related Publications
Our study assessed the methylation status of the SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes, which are associated with epigenetic silencing in cancers. In a group of 75 patients with oral squamous cell carcinoma, aberrant methylation was detected using methylation-specific PCR in tumours and matched margins. Our results showed significantly higher methylation frequency in tumours than in surgical margin of SFRP2 (26.6% vs 11.9%, p < 0.05) and DAPK1 (65.3% vs 41.3%, p < 0.01) genes. Moreover, methylation of the SFRP1 and DAPK1 genes was associated with older age. Advanced tumour stages were associated with lower rates of SFRP1 gene methylation. Decreased methylation levels of the SFRP2 and RASSF1A genes were associated with positive N stage. On the contrary, lymph node metastasis were associated with higher methylation rates of RARβ and DAPK1 genes. Patients with a familial history of cancer were associated with more frequently methylated SFRP1, SFRP2 and DAPK1 genes. Hypermethylation of DAPK1 was associated with decreased risk of death in patients. Our results are suggestive, although not conclusive, that some epigenetic changes, especially frequent hypermethylation of SFRP2 and DAPK1 genes, can be useful as potential diagnostic biomarkers of oral cavity cancer. Moreover, estimating the methylation status in surgical margins could become an additional strategy for more accurate treatment methods. Further efforts are needed to identify and validate this finding on a larger patient group and using new advanced methylation testing methods.

Qi M, Xiong X
Promoter hypermethylation of RARβ2, DAPK, hMLH1, p14, and p15 is associated with progression of breast cancer: A PRISMA-compliant meta-analysis.
Medicine (Baltimore). 2018; 97(51):e13666 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: Numerous studies have investigated the associations between RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation and clinical progression of patients with breast cancer, however the results remained uncertain due to the small sample size. Therefore, we performed a meta-analysis to explore the role of RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation in the susceptibility and clinical progression of breast cancer.
METHODS: Eligible studies were obtained by searching Medicine, Embase, Web of knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases. The odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation with breast cancer pathogenesis. Trial sequential analysis (TSA) was applied to observe the reliability of pooled results of RARβ2 gene, and obtain a conservative required information size (RIS).
RESULTS: In primary screened 445 articles, 39 literatures with 4492 breast cancer patients were finally enrolled in the final meta-analysis. The results indicated that the frequency of RARβ2 promoter hypermethylation in case group was significantly higher than the frequency of control group (OR = 7.21, 95% CI = 1.54-33.80, P < .05). The RARβ2 promoter hypermethylation had a significant association with lymph node metastasis of breast cancer (OR = 2.13, 95% CI = 1.04-4.47, P < .05). And, the RARβ2 promoter hypermethylation was more common in the breast cancer patients of TNM III-IV stage than those patients of TNM I-II stage (OR = 1.85, 95% CI = 1.33-2.57, P < .05). In addition, the promoter hypermethylation of DAPK, hMLH1, and p14 genes were significantly associated with the susceptibility of breast cancer (for DAPK, OR = 4.93, 95% CI = 3.17-7.65; for hMLH1, OR = 1.84, 95% CI = 1.26-1.29; for p14, OR = 22.52, 95% CI = 7.00-72.41; for p15, OR = 2.13, 95% CI = 0.30-15.07).
CONCLUSIONS: Our findings revealed that the RARβ2 promoter hypermethylation significantly increased the risk of breast cancer. In the meantime, the meta-analysis demonstrated that there were significant associations of RARβ2 promoter hypermethylation with lymph node metastasis and TNM-stage of breast cancer patients. In addition, DAPK, hMLH1, and p14 genes promoter hypermethylation were significantly associated with the susceptibility of breast cancer.

Chen M, Ye K, Zhang B, et al.
Paris Saponin II inhibits colorectal carcinogenesis by regulating mitochondrial fission and NF-κB pathway.
Pharmacol Res. 2019; 139:273-285 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Accumulating evidence suggests that mitochondrial dynamics are closely implicated in carcinogenesis including CRC. Paris Saponin II (PSII), a major steroidal saponin extracted from Rhizoma Paris polyphylla, has emerged as a potential anticancer agent. However, the effects of PSII on CRC and its underlying mechanisms remain unknown. In the present study, we found PSII induced apoptosis and inhibited colony formation in HT 29 and HCT 116 cells, and cell cycle arrest in G1 phase. PSII inhibited the phosphorylation of ERK1/2 and mitochondrial translocation of dynamin-related protein 1 (Drp1) by dephosphorylating Drp1 at Ser616, leading to the suppression of mitochondrial fission. PSII also suppressed NF-κB activation as a result of the inhibition of IKKβ and p65 translocation. Drp1 knockdown remarkably downregulated the nuclear expression of p65 and its target genes cyclin D1 and c-Myc in HCT 116 cell, confirming the link between mitochondrial fission and NF-κB pathway. Silencing of Drp 1 enhanced the inhibitory effects of PSII on p65 phosphorylation and the expressions of cyclin D1 and c-Myc, revealing that the inhibitory effects of PSII on cyclin D1 and c-Myc were relevant in the suppression of Drp1 and NF-κB activation. An in vivo study demonstrated PSII remarkably decreased the xenograft tumor size and suppressed the phosphorylation of ERK1/2 and Drp1 at Ser616. Taken together, our results suggested that PSII could inhibit colorectal carcinogenesis, at least in part, by regulating mitochondrial fission and NF-κB pathway.

Fiano V, Trevisan M, Fasanelli F, et al.
Methylation in host and viral genes as marker of aggressiveness in cervical lesions: Analysis in 543 unscreened women.
Gynecol Oncol. 2018; 151(2):319-326 [PubMed] Related Publications
OBJECTIVE: The present study aimed to evaluate the association between altered methylation and histologically confirmed high grade cervical intraepithelial neoplasia (hgCIN).
METHODS: Methylation levels in selected host (CADM1, MAL, DAPK1) and HPV (L1_I, L1_II, L2) genes were measured by pyrosequencing in DNA samples obtained from 543 women recruited in Curitiba (Brazil), 249 with hgCIN and 294 without cervical lesions. Association of methylation status with hgCIN was estimated by Odds Ratio (OR) with 95% confidence interval (CI).
RESULTS: The mean methylation level increased with severity of the lesion in the host and viral genes (p-trend < 0.05), with the exception of L1_II region (p-trend = 0.075). Positive association was found between methylation levels for host genes and CIN2 and CIN3 lesions respectively [CADM1: OR 4.17 (95%CI 2.03-8.56) and OR 9.54 (95%CI 4.80-18.97); MAL: OR 5.98 (95%CI 2.26-15.78) and OR 22.66 (95%CI 9.21-55.76); DAPK1: OR 3.37 (95%CI 0.93-12.13) and OR 6.74 (95%CI 1.92-23.64)]. Stronger risk estimates were found for viral genes [L1_I: OR 10.74 (95%CI 2.66-43.31) and OR 15.00 (95%CI 3.00-74.98); L1_II: OR 73.18 (95%CI 4.07-1315.94) and OR 32.50 (95%CI 3.86-273.65); L2: OR 4.73 (95%CI 1.55-14.44) and OR 10.62 (95%CI 2.60-43.39)]. The cumulative effect of the increasing number of host and viral methylated genes was associated with the risk of CIN2 and CIN3 lesions (p-trend < 0.001).
CONCLUSIONS: Our results, empowered by a wide cervical sample series with a large number of hgCIN, supported the role of methylation as marker of aggressiveness.

Thongchot S, Vidoni C, Ferraresi A, et al.
Dihydroartemisinin induces apoptosis and autophagy-dependent cell death in cholangiocarcinoma through a DAPK1-BECLIN1 pathway.
Mol Carcinog. 2018; 57(12):1735-1750 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is a very aggressive cancer arising from the malignant transformation of cholangiocytes. Intrahepatic CCA is associated with reactive inflammation and intense fibrosis of the hepatobiliary tract. Dihydroartemisinin (DHA), the active compound found in Artemisia annua, has been shown to possess anti-tumor activity in a variety of human cancers, including hepatoma. Here, we tested the ability of DHA to specifically kill CCA cells and have investigated the underlying mechanisms. DHA induced both apoptosis and autophagy-dependent caspase-independent cell death in many CCA cell lines, while being slightly toxic to immortalized cholangiocytes. DHA induced the expression of many apoptosis- and autophagy-related genes in CCA cells. In particular, it greatly induced the expression of DAPK1, and reduced the interaction of BECLIN1 with BCL-2 while promoting its interaction with PI3KC3. Genetic silencing of DAPK1 prevented DHA-induced autophagy. Pharmacologic and genetic inhibition of BECLIN1 function prevented autophagy and cell death induced by DHA in CCA cells. These data unravel a novel pathway of DHA cancer toxicity and open the possibility to introduce DHA in the therapeutic regimen for the treatment of CCA.

Huang X, Wu C, Fu Y, et al.
Methylation analysis for multiple gene promoters in non-small cell lung cancers in high indoor air pollution region in China.
Bull Cancer. 2018; 105(9):746-754 [PubMed] Related Publications
AIM: The prevalence and mortality rates of lung cancer in Xuanwei, Yunnan, China, are the highest in the world. The severe indoor air pollution caused by smoky coals with high benzo (a)pyrene (BaP) and quartz levels is the main environmental factor. The aim of this study was to investigate methylation profiles of promoters in eight genes in primary non-small cell lung cancers (NSCLC) exposed to smoky coals.
MATERIALS AND METHODS: Candidate genes including CDKN2A, DLEC1, CDH1, DAPK, RUNX3, APC, WIF1 and MGMT were determined for the promoter methylation status using Nested methylation-specific PCR (nMSP) in primary 23NSCLC tissues and in circulating tumor DNA (ctDNA) isolated from 42plasma samples (9matched to tissues) as well as 10healthy plasma samples, using Sanger sequencing to verify the results.
RESULTS: Seven of the 8genes, except MGMT, had relatively high methylation frequencies ranging from 39%-74% in tissues. Moreover, methylation frequencies in five genes identified in lung cancer plasma were 45% for CDKN2A, 48% for DLEC1, 76% for CDH1, 14% for DAPK, 29% for RUNX3, with a relatively good concordance of methylation among 9 tissues and paired plasma. However, the genes from all healthy plasma showed no methylation.
CONCLUSIONS: A panel of genes including CDKN2A, DLEC1, CDH1, DAPK and RUNX3 may be used as potential epigenetic biomarkers for early lung cancer detection. CDH1 promoter methylation was associated with lung cancer metastasis in areas of air pollution from buring of smoky coals. DLEC1 and CDH1 exhibited specific high methylation frequencies, different from previous reports.

Dvojakovska S, Popovic-Monevska D, Grcev A, et al.
Promotor hypermethylated genes: Prospective diagnostic biomarkers in oral cancerogenesis.
J Craniomaxillofac Surg. 2018; 46(10):1737-1740 [PubMed] Related Publications
The advancements in epigenetics of oral squamous cell carcinoma (OSCC), are made in regard to DNA hypermethylation of MGMT, DAPK, ECAD (E-cadherin) and p16, as an important component of oral carcinogenesis and new potential biomarkers in molecular diagnostic strategies. The objective of the study was to evaluate the methylation status of the proposed genes and their possible role in the tumor genesis and diagnosis of OSCC.
MATERIALS AND METHODS: From sixty surgically treated and molecularly analyzed patients, we obtained three groups of bioptical materials: tumor, normal contralateral and healthy tissues. Comparison of the frequencies of DNA methylation for all transcripts was utilized to validated their potential role in the cancerogenesis and detection of OSCC.
RESULTS: The most often methylated genes in the tumor samples were ECAD, MGMT, DAPK followed by p16 genes (90% vs 75% vs 75% vs 52,5%), respectively. We observed frequent methylated genes in contralateral mucosa and consistently unmethylated- 0% in healthy samples. ECAD methylated genes showed the highest sensitivity for diagnosing OSCC in tumor and contralateral tissues (90% and 89,7% respectively, with a specificity of 100%).
CONCLUSION: ECAD and MGMT have tumor-specific signatures and can be considered as potential noninvasive diagnostic biomarkers in OSCC.

Özdemir İ, Pınarlı FG, Pınarlı FA, et al.
Epigenetic silencing of the tumor suppressor genes SPI1, PRDX2, KLF4, DLEC1, and DAPK1 in childhood and adolescent lymphomas.
Pediatr Hematol Oncol. 2018; 35(2):131-144 [PubMed] Related Publications
The aim of the study was to investigate the expression and methylation status of seven distinctive genes with tumor suppressing properties in childhood and adolescent lymphomas. A total of 96 patients with Hodgkin Lymphoma (HL, n = 41), Non-Hodgkin Lymphoma (NHL, n = 15), and reactive lymphoid hyperplasia (RLH, n = 40, as controls) are included in the research. The expression status of CDKN2A, SPI1, PRDX2, DLEC1, FOXO1, KLF4 and DAPK1 genes were measured with QPCR method after the RNA isolation from paraffin blocks of tumor tissue and cDNA conversion. DNA isolation was performed from samples with low gene expression followed by methylation PCR study specific to promoter regions of these genes. We found that SPI1, PRDX2, DLEC1, KLF4, and DAPK1 genes are significantly less expressed in patient than the control group (p = 0.0001). However, expression of CDKNA2 and FOXO1 genes in the patient and control groups were not statistically different. The methylation ratios of all genes excluding the CDKN2A and FOXO1 were significantly higher in the HL and NHL groups than the controls (p = 0.0001). We showed that SPI1, PRDX2, DLEC1, KLF4 and DAPK1 genes are epigenetically silenced via hypermethylation in the tumor tissues of children with HL and NHL. As CDKN2A gene was not expressed in both patient and control groups, we conclude that it is not specific to malignancy. As FOXO1 gene was similarly expressed in both groups, its relationship with malignancy could not be established. The epigenetically silenced genes may be candidates for biomarkers or therapeutic targets in childhood and adolescent lymphomas.

Chen X, Zhang S, Wang Z, et al.
Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway.
J Exp Clin Cancer Res. 2018; 37(1):128 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Hypoxia triggers the epithelial-mesenchymal transition (EMT) of cancer cells, which enhances their malignant character and elevates metastatic risk. Supervillin associates tightly with the membrane and cytoskeleton, promoting cell motility, invasiveness, and cell survival. However, the roles of supervillin in HCC metastasis remain unclear.
METHODS: Tissue microarray technology was used to immunohistochemically stain for supervillin antibody in 173 HCC tissue specimens and expression levels correlated with the clinicopathological variables. Tumor cell motility and invasiveness, as well as changes in the mRNA expression levels of genes associated with cancer cell EMT, were investigated. The relationship between supervillin and Rho GTPases was examined using Co-IP and GST pull-down.
RESULTS: Hypoxia-induced upregulation of supervillin promoted cancer cell migration and invasion via the activation of the ERK/p38 pathway downstream of RhoA/ROCK signaling. Furthermore, supervillin regulated the expression of EMT genes during hypoxia and accelerated the metastasis of HCC in vivo.
CONCLUSIONS: Hypoxia-induced increase in supervillin expression is a significant and independent predictor of cancer metastasis, which leads to poor survival in HCC patients. Our results suggest that supervillin may be a candidate prognostic factor for HCC and a valuable target for therapy.

Li X, Pu J, Liu J, et al.
The prognostic value of DAPK1 hypermethylation in gliomas: A site-specific analysis.
Pathol Res Pract. 2018; 214(7):940-948 [PubMed] Related Publications
BACKGROUND AND AIMS: The 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.
METHODS: Based 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.
RESULTS: Methylation 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.
CONCLUSION: Analysis 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.

Cui Z, An X, Li J, et al.
LncRNA MIR22HG negatively regulates miR-141-3p to enhance DAPK1 expression and inhibits endometrial carcinoma cells proliferation.
Biomed Pharmacother. 2018; 104:223-228 [PubMed] Related Publications
Emerging evidence has indicated that long non-coding RNAs (lncRNAs) play critical roles in tumor development and progression. Recent studies reported that lncRNA MIR22HG could play important roles in hepatocellular carcinoma and lung cancer progression. However, the expression and underlying mechanism of MIR22HG in endometrial cancer (EC) remain unclear. In the present study, qRT-PCR showed that MIR22HG expression was significantly downregulated in EC tissues. In vitro function assays showed that increased MIR22HG expression significantly inhibited EC cells proliferation, induced EC cells apoptosis, and arrested EC cells in G0/G1 phase. Furthermore, miR-141-3p was identified and confirmed to be the target of MIR22HG. Subsequently, DAPK1 was confirmed to be regulated by MIR22HG and miR-141-3p, and could play a positive role in inhibiting EC cells proliferation. Collectively, these data demonstrated that lncRNA MIR22HG could act as a tumor suppressor and inhibited EC cells proliferation through regulating miR-141-3p/DAPK1 axis, which provides a new therapeutic target for EC treatment.

Yang XY, Zhang J, Yu XL, et al.
Death-associated protein kinase promoter methylation correlates with clinicopathological and prognostic features in nonsmall cell lung cancer patients: A cohort study.
J Cancer Res Ther. 2018; 14(Supplement):S65-S71 [PubMed] Related Publications
Objective: 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.
Materials and Methods: 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).
Results: 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%, χ
Conclusion: Our results showed that DAPK promoter methylation is tightly correlated with clinicopathological features of NSCLC and is associated with poor prognosis in patients.

Yadav P, Masroor M, Nandi K, et al.
Promoter Methylation of BRCA1, DAPK1 and RASSF1A is Associated with Increased Mortality among Indian Women with Breast Cancer
Asian Pac J Cancer Prev. 2018; 19(2):443-448 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Background: Promoter methylation has been observed for several genes in association with cancer development and progression. Hypermethylation mediated-silencing of tumor suppressor genes (TSGs) may contribute to breast cancer pathogenesis. The present study was conducted to investigate the promoter methylation status of BRCA1, DAPK1 and RASSF1A genes in Indian women with breast cancer. Materials and Methods: Promoter methylation was evaluated in DNA extracted from mononuclear cells (MNCs) in peripheral blood samples of 60 histopathologically confirmed newly diagnosed, untreated cases of breast cancer as well as 60 age and sex matched healthy controls using MS-PCR. Association of promoter methylation with breast cancer-specific mortality was analyzed with Cox proportional hazards models. Kaplan-Meier survival analysis was performed for overall survival of the breast cancer patients. Results: We observed a significant increase of BRCA1, DAPK1 and RASSF1A promoter methylation levels by 51.7% (P <0.001), 55.0% (P <0.001) and 46.6% (P <0.001), respectively, when compared to healthy controls. A strong correlation was noted between hypermethylation of the tumor suppressor genes BRCA1 (P= 0.009), DAPK1 (P= 0.008) and RASSF1A (P= 0.02)) with early and advanced stages of breast cancer patients. We also found that breast cancer-specific mortality was significantly associated with promoter methylation of BRCA1 [HR and 95% CI: 3.25 (1.448-7.317)] and DAPK1 [HR and 95% CI: 2.32 (1.05-5.11)], whereas limited significant link was evident with RASSF1A [HR and 95% CI: 1.54 (0.697-3.413]. Conclusion: Our results suggest that promoter methylation of BRCA1, DAPK1 and RASSF1A genes may be associated with disease progression and poor overall survival of Indian women with breast cancer.

Akhtar B, Muhammad F, Sharif A, et al.
Diverse Signaling Pathways and Current Status of Molecular Targeted Treatments for Hepatocellular Carcinoma.
Crit Rev Eukaryot Gene Expr. 2017; 27(4):373-385 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the leading causes of death associated with cancer. Various molecular mechanisms are involved in HCC development. Alterations in these molecular mechanisms include chromosomal instability, gene mutations, and variations in protein expressions. A number of cell signaling pathways that are associated with the occurrence of apoptosis, cell proliferation, and angiogenesis provide new prospects for the development of HCC treatments. Newly designed, potential therapeutic regimens target specific receptors, kinases, and vital proteins. Sorafenib is the only FDA-approved drug for HCC treatment, and it has been found that the complex genomic aberrations in HCC can be overcome using combination therapy. For example, therapeutic benefits have been gained using sorafenib with doxorubicin, oxaliplatin, cisplatin, and monoclonal antibodies. In addition, elumetinib, carbozantinib, and refametinib may be effective when used in combination with sorafenib. Drugs that target several signaling pathways have shown promising results in phase 3 clinical trials, and clinical studies using these drugs have changed the management strategy for HCC, particularly with the use of combination therapeutic regimens. Such research has improved the current standards of care and influenced clinical decision making.

Humbert M, Federzoni EA, Tschan MP
Distinct TP73-DAPK2-ATG5 pathway involvement in ATO-mediated cell death versus ATRA-mediated autophagy responses in APL.
J Leukoc Biol. 2017; 102(6):1357-1370 [PubMed] Related Publications
We have previously demonstrated that the death-associated protein kinase 2 (DAPK2) expression is significantly reduced in acute myeloid leukemia (AML), particularly in acute promyelocytic leukemia (APL) blast cells. In this study, we aimed at further understanding DAPK2 function and regulation during arsenic trioxide (ATO) cytotoxic or all-trans retinoic acid (ATRA) differentiation therapy in APL cells. We found that the p53 family member transactivation domain-p73 isoform (TAp73) binds to and activates the

Li B, Wang W, Li Z, et al.
MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression.
Cancer Lett. 2017; 410:212-227 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Cisplatin (CDDP) resistance is a major clinical problem associated with poor prognosis in gastric cancer (GC) patients. In this study, we performed integrated analysis of TCGA data from microRNAs (miRNAs) expression matrix of GC patients who received CDDP-based chemotherapy with GEO dataset which contains differential miRNAs expression profiles in CDDP-resistant and -sensitive cell lines. We identified miR-148a-3p downregulation as a key step involved in CDDP resistance. Using a cohort consisting 105 GC patients who received CDDP-based therapy, we found that miR-148a-3p downregulation was associated with a decrease in patients' disease-free survival (DFS, P = 0.0077). A series of experiment data demonstrated that: 1) miR-148a-3p was downregulated in CDDP-resistant GC cell lines; 2) miR-148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AKAP1 expression level; 3) AKAP1 played a novel role in CDDP resistance by inhibiting P53-mediated DRP1 dephosphorylation; 4) miR-148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. Taken together, our study demonstrates that miR-148a-3p could be a promising prognostic marker or therapeutic candidate for overcoming CDDP resistance in GC.

Yuan W, Chen J, Shu Y, et al.
Correlation of DAPK1 methylation and the risk of gastrointestinal cancer: A systematic review and meta-analysis.
PLoS One. 2017; 12(9):e0184959 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
OBJECTIVE: One of the critical mechanisms of gastrointestinal cancer pathogenesis is the silencing of death associated protein kinase 1 (DAPK1), which could be caused by aberrant methylation of the promoter. However, the relationship between DAPK1 methylation and the risk of gastrointestinal cancer is still controversial. Hence, we conducted this study to determine the potential correlation.
METHODS: Eligible publications were searched in the Pubmed, Embase, and Cochrane Library through November 2016 according to the inclusion criteria and exclusion criteria. Revman 5.3 and Stata 12.0 software were used to analyze the relevant data regarding the association between the frequency of DAPK1 methylation and gastrointestinal cancer.
RESULTS: A total of 22 studies with 2406 patients were included in this meta analysis. Methylation of DAPK1 was positively related with the risk of gastrointestinal cancer (odds ratio [OR] = 5.35, 95% confidence interval [CI]: 2.76-10.38, P<0.00001, random effects model). The source of heterogeneity was analyzed by sensitivity analysis and subgroup analysis. After omitting one heterogeneous study, the I2 decreased and the OR increased in pooled analysis. Also, the heterogeneity decreased most significantly in the subgroup of studies that had a sample size of less than 60 cases. Then, the correlations between DAPK1 methylation and clinicopathological features of gastrointestinal cancer were assessed. DAPK1 methylation was positively correlated with the lymph node (N) stage (positive vs. negative, OR = 1.45, 95%CI: 1.01-2.06, P = 0.04, fixed effects model) and poor differentiation (OR = 1.55, 95%CI: 1.02-2.35, P = 0.04, fixed effects model) in gastric cancer, and the association was significant among Asian patients. However, among cases of gastrointestinal cancer, the association between DAPK1 methylation and tumor (T) stage, N stage, distant metastasis (M) stage, and cancer differentiation were not statistically significant.
CONCLUSIONS: DAPK1 methylation is a potential biomarker for the early diagnosis of gastrointestinal cancer. Further analysis of the clinicopathological features indicated that aberrant methylation of DAPK1 is positively associated with the tumorigenesis of gastrointestinal cancer, and metastasis of gastric cancer.

Kitamura S, Yanagi T, Imafuku K, et al.
Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma.
J Dermatol Sci. 2017; 88(3):298-307 [PubMed] Related Publications
BACKGROUND: Dynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC).
OBJECTIVE: To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs.
METHODS AND RESULTS: We investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1. The Drp1 gene-knockdown SCC cells showed lower cell proliferation than scramble-control cells, as assessed by direct cell counting and clonogenic assays. DNA content analysis showed Drp1 knockdown to cause G2/M arrest. Morphologically, the depletion of Drp1 resulted in an elongated, hyper-fused mitochondrial network. The MEK inhibitor PD325901 suppressed cell proliferation, as well as inhibiting the phosphorylation of ERK
CONCLUSION: Our results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies.

Tan J, Jiang X, Yin G, et al.
Anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway.
Oncol Rep. 2017; 38(3):1373-1382 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Anacardic acid, which is commonly seen in plants of Anacardiaceae, is an important composition of cashew, ginkgo leaf and fruit, and it has been suggested in previous research to show antitumor activity. The main aim of the present study was to evaluate the anticancer effects of anacardic acid on cell apoptosis of prostatic cancer and molecular mechanisms of this phenomenon. In this study we found that anacardic acid inhibited cell proliferation, induced apoptosis and caspase-3/9 activities and Bax protein expression of prostatic cancer. Anacardic acid induced the ER stress inducing factors (BiP, CHOP, p-eIF2α), autophagy, LC3, Beclin-1, Atg 7 and DAPK3 protein expression, and suppressed p-Akt and p-mTOR protein expression of prostatic cancer. Si-CHOP was used to inhibit ER stress in prostatic cancer by anacardic acid, which showed that the cell proliferation was increased, apoptosis, and caspase-3/9 activities and Bax protein expression was suppressed, autophagy, LC3, Beclin-1, Atg 7 and DAPK3 protein expression was reduced, and p-Akt and p-mTOR protein expression was promoted. DAPK3 inhibited p-Akt and p-mTOR protein expression, enhanced the anticancer effects of anacardic acid on prostatic cancer through autophagy. For the first time, the present study showed that anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway.

Ha BG, Jung SS, Shon YH
Effects of proton beam irradiation on mitochondrial biogenesis in a human colorectal adenocarcinoma cell line.
Int J Oncol. 2017; 51(3):859-866 [PubMed] Related Publications
Proton beam therapy has recently been used to improve local control of tumor growth and reduce side-effects by decreasing the global dose to normal tissue. However, the regulatory mechanisms underlying the physiological role of proton beam radiation are not well understood, and many studies are still being conducted regarding these mechanisms. To determine the effects of proton beams on mitochondrial biogenesis, we investigated: mitochondrial DNA (mtDNA) mass; the gene expression of mitochondrial transcription factors, functional regulators, and dynamic-related regulators; and the phosphorylation of the signaling molecules that participate in mitochondrial biogenesis. Both the mtDNA/nuclear DNA (nDNA) ratio and the mitochondria staining assays showed that proton beam irradiation increases mitochondrial biogenesis in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced aggressive HT-29 cells. Simultaneously, proton beam irradiation increases the gene expression of the mitochondrial transcription factors PGC-1α, NRF1, ERRα, and mtTFA, the dynamic regulators DRP1, OPA1, TIMM44, and TOM40, and the functional regulators CytC, ATP5B and CPT1-α. Furthermore, proton beam irradiation increases the phosphorylation of AMPK, an important molecule involved in mitochondrial biogenesis that is an energy sensor and is regulated by the AMP/ATP ratio. Based on these findings, we suggest that proton beam irradiation inhibits metastatic potential by increasing mitochondrial biogenesis and function in TPA-induced aggressive HT-29 cells.

Kuo CW, Tsai MH, Lin TK, et al.
mtDNA as a Mediator for Expression of Hypoxia-Inducible Factor 1α and ROS in Hypoxic Neuroblastoma Cells.
Int J Mol Sci. 2017; 18(6) [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Mitochondria consume O₂ to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1α pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (ρ⁰) cells of neuroblastoma were cultured in a hypoxic chamber to simulate a hypoxic condition and then the major components involved in mitochondrial related pathways, hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) were measured. The results showed that hypoxia-stimulated exposure elevated expression of HIF-1α, which was additionally influenced by level of generated ROS within the cytosol. Moreover, elevation of HIF-1α also resulted in increases of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase kinase 1 (PDK1) in both hypoxic cells. The expression of mitochondrial biogenesis related proteins and metabolic components were noted to increase significantly in hypoxic SK-N-AS cells, indicating that mtDNA was involved in mitochondrial retrograde signaling and metabolic pathways. An analysis of dynamic proteins found elevated levels of HIF-1α causing an increased expression of dynamin-related protein 1 (DRP1) during hypoxia; further, the existence of mtDNA also resulted in higher expression of DRP1 during hypoxia. By using siRNA of HIF-1α or DRP1, expression of DRP1 decreased after suppression of HIF-1α; moreover, the expression of HIF-1α was also affected by the suppression of DRP1. In this study, we demonstrated that mtDNA is a mediator of HIF-1α in eliciting metabolic reprogramming, and mitochondrial biogenesis. Identification of a mutual relationship between HIF-1α and DRP1 may be a critical tool in the future development of clinical applications.

Qiao P, Zhao F, Liu M, et al.
Hydrogen sulfide inhibits mitochondrial fission in neuroblastoma N2a cells through the Drp1/ERK1/2 signaling pathway.
Mol Med Rep. 2017; 16(1):971-977 [PubMed] Related Publications
Hydrogen sulfide (H2S) has been demonstrated to have various effects on mitochondrial function. The aim of the present study was to investigate the effects of H2S on mitochondrial fission and the potential underlying mechanisms of these effects. Transmission electron microscopy analysis demonstrated that sodium hydrosulfide (NaHS, a donor of H2S) inhibited mitochondrial fission in a dose‑ and time‑dependent manner. Treating neuro‑2a (N2a) mouse neuroblastoma cells with 400 µM NaHS for 16 h significantly increased the % of elongated mitochondria and reduced the number of mitochondria per cell compared with untreated cells. In addition, the viability and ATP generation of N2a cells that were treated with various concentrations of NaHS was examined. The results demonstrated that treatment with 400 and 600 µM NaHS increased cell viability and ATP generation compared with untreated cells. To further understand the effects of H2S on mitochondrial morphology, the protein and mRNA expression levels of dynamin 1 like (Dnm1l, also known as Drp1) were examined, and the results demonstrated that NaHS dose‑dependently reduced Drp1 mRNA and protein levels, consistent with the mitochondrial morphology changes. To determine whether H2S affects mitochondrial morphology through Drp1 expression, Drp1 was overexpressed in N2a cells using a lentivirus encoding the Drp1 cDNA. It was observed that Drp1 overexpression reversed the effects of NaHS. Furthermore, NaHS promoted the phosphorylation of extracellular signal‑regulated kinase (ERK) 1/2, and the effects of NaHS on Drp1 expression were abolished by an ERK1/2 inhibitor (PD98059). The results of the present study indicate that the H2S‑induced decrease in Drp1 mRNA and protein levels and mitochondrial fission may involve the ERK1/2 signaling pathway. The present study suggests that H2S may be used in the future as a potential therapeutic for diseases that may be mediated by abnormal mitochondria fragmentation, such as Alzheimer's disease.

Cook SJ, Stuart K, Gilley R, Sale MJ
Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling.
FEBS J. 2017; 284(24):4177-4195 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
The ERK1/2 signalling pathway is best known for its role in connecting activated growth factor receptors to changes in gene expression due to activated ERK1/2 entering the nucleus and phosphorylating transcription factors. However, active ERK1/2 also translocate to a variety of other organelles including the endoplasmic reticulum, endosomes, golgi and mitochondria to access specific substrates and influence cell physiology. In this article, we review two aspects of ERK1/2 signalling at the mitochondria that are involved in regulating cell fate decisions. First, we describe the prominent role of ERK1/2 in controlling the BCL2-regulated, cell-intrinsic apoptotic pathway. In most cases ERK1/2 signalling promotes cell survival by activating prosurvival BCL2 proteins (BCL2, BCL-x

Jin X, Wang J, Gao K, et al.
Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer.
PLoS Genet. 2017; 13(4):e1006748 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer.

Zhou TJ, Zhang SL, He CY, et al.
Downregulation of mitochondrial cyclooxygenase-2 inhibits the stemness of nasopharyngeal carcinoma by decreasing the activity of dynamin-related protein 1.
Theranostics. 2017; 7(5):1389-1406 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Cancer stem cells (CSCs) are a small subset of malignant cells, possessing stemness, with strong tumorigenic capability, conferring resistance to therapy and leading to the relapse of nasopharyngeal carcinoma (NPC). Our previous study suggested that cyclooxygenase-2 (COX-2) would be a novel target for the CSCs-like side population (SP) cells in NPC. In the present study, we further found that COX-2 maintained the stemness of NPC by enhancing the activity of mitochondrial dynamin-related protein 1 (Drp1), a mitochondrial fission mediator, by studying both sorted SP cells from NPC cell lines and gene expression analyses in NPC tissues. Using both overexpression and knockdown of COX-2, we demonstrated that the localization of COX-2 at mitochondria promotes the stemness of NPC by recruiting the mitochondrial translocation of p53, increasing the activity of Drp1 and inducing mitochondrial fisson. Inhibition of the expression or the activity of Drp1 by siRNA or Mdivi-1 downregulates the stemness of NPC. The present study also found that inhibition of mitochondrial COX-2 with resveratrol (RSV), a natural phytochemical, increased the sensitivity of NPC to 5-fluorouracil (5-FU), a classical chemotherapy drug for NPC

Loginov VI, Pronina IV, Burdennyi AM, et al.
Role of Methylation in the Regulation of Apoptosis Genes APAF1, DAPK1, and BCL2 in Breast Cancer.
Bull Exp Biol Med. 2017; 162(6):797-800 [PubMed] Related Publications
Changes in the levels of expression of proapoptotic genes APAF1 and DAPK1 and antiapoptotic gene BCL2 were studied by real time PCR in specimens of tumors and histologically intact tissue from 28 patients with breast cancer. The expression of APAF1 and DAPK1 was below the normal in the majority of tumor samples (p<0.05), while the level of BCL2 mRNA more often surpassed the normal (p<0.1). Study of the same sample of specimens by methylspecific PCR showed predominance of APAF1 and DAPK1 hypermethylation (p<0.05 and p<0.1, respectively) and more frequent hypomethylation of BCL2. A significant correlation between changes in the levels of expression and methylation (r=0.40-0.49; p<0.05) was detected for all three genes (APAF1, DAPK1, and BCL2). The results suggest that methylation play an important role in the regulation of these apoptosis system genes in breast cancer.

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