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- Title
Functional characterization of a promoter polymorphism in APE1/Ref-1 that contributes to reduced lung cancer susceptibility.
- Authors
Juan Lu; Shuyu Zhang; Dan Chen; Huibo Wang; Wenting Wu; Xiaotian Wang; Yunping Lei; Jiucun Wang; Ji Qian; Weiwei Fan; Zhibin Hu; Li Jin; Hongbing Shen; Wei Huang; Qingyi Wei; Daru Lu
- Abstract
Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) is a ubiquitous multifunctional protein that possesses both DNA-repair and redox regulatory activities. Although it was originally identified as a DNA-repair enzyme, accumulating evidence supports a role of APE1/Ref-1 in tumor development. To investigate association between APE1/ Ref-1 polymorphisms and lung cancer risk in Chinese populations, we first genotyped three variants of APE1/ Ref-1 and found a -141 T-to-G variant (rs1760944) in the promoter associated with decreased risk of lung cancer [odds ratio (OR) = 0.62 for GG; P=0.043]. Similar results were obtained in a follow-up replication study. Combined data from the two studies comprising a total of 1072 lung cancer patients and 1064 cancer-free control participants generated a more significant association (P=0.002). We observed lower APE1/Ref-1 mRNA levels in the presence of the protective G allele in human peripheral blood mononuclear cells and normal lung tissues. The -141G-allele-promoter construct exhibited decreased luciferase reporter gene expression. Electrophoretic mobility shift assays and surface plasmon resonance analysis showed that the -141G allele impaired the binding affinity of some transcription factor, accounting for lower APE1/Ref-1-promoter activity. Supershift assays further revealed that the protein of interest was octamer-binding transcription factor-1 (Oct-l). Chromatin immunoprecipitation reconfirmed binding of Oct-1 to the APE1/Ref-1-141-promoter region. We also found that Oct-1 conferred attenuated transactivation capacity toward the -141G variant by exogenously introducing Oct-1. These data indicate that genetic variations in APE1/Ref-1 may modify susceptibility to lung cancer and provide new insights into an unexpected effect of APE1/Ref-1 on lung carcinogenesis.
- Subjects
CHINA; GENETIC polymorphisms; PROMOTERS (Genetics); ENDONUCLEASES; GENETICS of disease susceptibility; LUNG cancer; CARCINOGENESIS
- Publication
FASEB Journal, 2009, Vol 23, Issue 10, p3459
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.09-136549