ZAR1 is a novel epigenetically inactivated tumour suppressor in lung cancer.

BACKGROUND

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.

RESULTS

In 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 is expressed in normal lung but inactivated by promoter methylation in lung cancer. is hypermethylated in primary lung cancer samples (22% small cell lung carcinoma (SCLC) and 76% non-small cell lung carcinoma (NSCLC),  < 0.001) vs. normal control lung tissue (11%). In lung cancer cell lines, was significantly methylated in 75% of SCLC and 83% of NSCLC vs. normal tissue ( < 0.005/0.05). In matching tumours and control tissues, we observed that NSCLC primary tumour samples exhibited a tumour-specific promoter methylation of in comparison to the normal control lung tissue. Demethylation treatment of various lung cancer cell lines reversed promoter hypermethylation and subsequently re-established expression. In addition, we could show the growth inhibitory potential of ZAR1 in lung cancer cell lines and cancer cell lines. Exogenous expression of not only inhibited colony formation but also blocked cell cycle progression of cancer cell lines.

CONCLUSIONS

Our study shows for the first time the lung tumour-specific epigenetic inactivation of 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.