title: Functional characterization of a promoter polymorphism in APE1/Ref-1 that contributes to reduced lung cancer susceptibility.
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-1). 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.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Wang
authors.forename: Yunping
authors.initials: Y
authors.lastname: Lei
authors.forename: Jiucun
authors.initials: J
authors.lastname: Wang
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
mesh_terms: D000328:Adult; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase