Hypermethylation-mediated partial transcriptional silencing of DAP-kinase gene in bladder cancer.
Death-associated protein kinase (DAP-kinase) is a novel serine/threonine kinase whose expression is required for interferon-gamma-induced apoptosis. This study evaluated the methylation pattern and its impact on the expression of the DAP-kinase gene in transitional cell carcinoma of the bladder as hypermethylation is one of the earliest and most frequent alterations leading to cancer. The frequency of hypermethylation of the gene promoter was 37.8%. On correlation with clinicopathological features, methylation was seen mostly in superficial tumours in the group aged > 60 years (42.9 vs 33.3% of those <or= 60 years) and in smokers (48.1 vs 27.4% of non-smokers). The increased risk of bladder cancer was 6.70-fold (95% confidence interval (CI) 2.09-23.87; p = 0.000) in those carrying methylated DAP-kinase and it was elevated in patients who smoked (odds ratio 7.87; 95% CI 1.50-54.96; p = 0.007). This study demonstrated that methylation in the gene promoter on its own could significantly decrease the mRNA expression level of DAP-kinase by 27.68%. Interestingly, patients within the group aged > 60 years and with a smoking habit showed increased downregulation of mRNA compared with non-smokers of this age group (similar pattern of methylation). Hypermethylation can decrease the expression of DAP-kinase and may be one of the reasons for conversion of normal cells to malignant cells, as the frequency of methylation at the early stage (superficial) of tumours was elevated. Methylation of DAP-kinase can be considered as one of the prognosis indicators for progression and development of bladder cancer.
Sobti
Ranbir Chander
RC
Department of Biotechnology, Panjab University, Chandigarh, India.
MalekZadeh
Kianoosh
K
Nikbakht
Mohsen
M
Sadeghi
Irandokht Asadi
IA
Shekari
Mohammad
M
Singh
Shrawan Kumar
SK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012907:Smoking / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D012333:RNA, Messenger; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases