Exp Mol Med.
2016 Jul;48(7):e246. 10.1038/emm.2016.50.
A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility
- Affiliations
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- 1Department of Biological Science, Dong-A University, Busan, Korea. shleem@dau.ac.kr
- 2Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
- 3Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Korea.
- 4Drug & Disease Target Team, Korea Basic Science Institute, Daejeon, Korea.
- 5Department of Pathology, Kosin University College of Medicine, Busan, Korea.
- 6Developmental Therapeutic Branch, National Cancer Institute, Bethesda, MD, USA.
- KMID: 2361533
- DOI: http://doi.org/10.1038/emm.2016.50
Abstract
- Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case-control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02-4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer.
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