Abstract
BackgroundLung cancer is the leading cause of cancer-related deaths with 1.8 million new cases each year and poor 5-year prognosis. Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby can promote cancer development and progression.ResultsIn this study, we analysed ZAR1 (zygote arrest 1), which has been said to be a maternal-effect gene and its expression mostly limited to certain reproductive tissues. Our study shows that ZAR1 is expressed in normal lung but inactivated by promoter methylation in lung cancer. ZAR1 is hypermethylated in primary lung cancer samples (22% small cell lung carcinoma (SCLC) and 76% non-small cell lung carcinoma (NSCLC), p < 0.001) vs. normal control lung tissue (11%). In lung cancer cell lines, ZAR1 was significantly methylated in 75% of SCLC and 83% of NSCLC vs. normal tissue (p < 0.005/0.05). In matching tumours and control tissues, we observed that NSCLC primary tumour samples exhibited a tumour-specific promoter methylation of ZAR1 in comparison to the normal control lung tissue. Demethylation treatment of various lung cancer cell lines reversed ZAR1 promoter hypermethylation and subsequently re-established ZAR1 expression. In addition, we could show the growth inhibitory potential of ZAR1 in lung cancer cell lines and cancer cell lines. Exogenous expression of ZAR1 not only inhibited colony formation but also blocked cell cycle progression of cancer cell lines.ConclusionsOur study shows for the first time the lung tumour-specific epigenetic inactivation of ZAR1 due to DNA methylation of its CpG island promoter. Furthermore, ZAR1 was characterised by the ability to block tumour growth through the inhibition of cell cycle progression in cancer cell lines. We propose that ZAR1 could serve as an epigenetically inactivated biomarker in lung cancer.
Highlights
Lung cancer is the leading cause of cancer-related deaths with 1.8 million new cases each year and poor 5-year prognosis
ZAR1 was amongst the most strongly deregulated genes, and up to date, no study investigated the epigenetic inactivation of the ZAR1 promoter and its consequences in lung cancer
We found that ZAR1 is expressed in normal lung (Fig. 1b), but its expression is lost in lung cancer cell lines (Fig. 1a, b)
Summary
Lung cancer is the leading cause of cancer-related deaths with 1.8 million new cases each year and poor 5-year prognosis. Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby can promote cancer development and progression. Lung cancer has a high incidence coupled with a poor 5-year survival rate of less than 17% [2]. In 2012, 1.8 million cases were newly diagnosed worldwide and 1.6 million deaths from lung cancer occurred [3]. Tobacco smoking still is the main cause for lung cancer development [4]. We found the maternal effect gene ZAR1 was one of the best candidates [8]. Human ZAR1 or zygote arrest 1 is located on chromosome 4 (4p11) and covered by a 1.5 kb large CpG island (Additional file 1: Figure S1). ZAR1’s 1275 nt transcript from 4 exons encodes 424 amino acid
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
