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A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer.

Publication ,  Journal Article
Zhang, S; Lu, J; Zhao, X; Wu, W; Wang, H; Lu, J; Wu, Q; Chen, X; Fan, W; Chen, H; Wang, F; Hu, Z; Jin, L; Wei, Q; Shen, H; Huang, W; Lu, D
Published in: Carcinogenesis
July 2010

Checkpoint kinase (CHEK) 2, a tumor suppressor gene, plays an essential role in the DNA damage checkpoint response cascade. We first investigated two polymorphisms in the proximal promoter of the CHEK2 gene and evaluated their associations with the risk of lung cancer in a case-control study using 500 incident lung cancer cases and 517 cancer-free controls. We found that CHEK2 rs2236141 -48 G > A was significantly associated with lung cancer risk (P = 0.0018). Similar results were obtained in a follow-up replication study in 575 lung cancer patients and 589 controls (P = 0.042). Quantitative polymerase chain reaction showed that individuals with the G allele had lower levels of CHEK2 transcripts in peripheral blood mononuclear cells and normal lung tissues. The -48 G-->A variant eliminated a methylation site and thereby relieve the transcriptional repression of CHEK2. Therefore, this polymorphism affected downstream transcription through genetic and epigenetic modifications. Luciferase reporter assays demonstrated that the major G allele significantly attenuated reporter gene expression when methylated. Electrophoretic Mobility shift assays and surface plasmon resonance revealed that the methylated G allele increased transcription factor accessibility. We used in vivo chromatin immunoprecipitation to confirm that the relevant transcription factor was Sp1. Using lung tissue heterozygous for the G/A single-nucleotide polymorphism, we found that Sp1 acted as a repressor and had a stronger binding affinity for the G allele. These results support our hypothesis that the CHEK2 rs2236141 variant modifies lung cancer susceptibility in the Chinese population by affecting CHEK2 expression.

Duke Scholars

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

July 2010

Volume

31

Issue

7

Start / End Page

1251 / 1258

Location

England

Related Subject Headings

  • Transcription, Genetic
  • Sp1 Transcription Factor
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Middle Aged
  • Male
  • Lung Neoplasms
 

Citation

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Zhang, S., Lu, J., Zhao, X., Wu, W., Wang, H., Wu, Q., … Lu, D. (2010). A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer. Carcinogenesis, 31(7), 1251–1258. https://doi.org/10.1093/carcin/bgq089
Zhang, Shuyu, Juan Lu, Xueying Zhao, Wenting Wu, Huibo Wang, Jun Lu, Qihan Wu, et al. “A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer.Carcinogenesis 31, no. 7 (July 2010): 1251–58. https://doi.org/10.1093/carcin/bgq089.
Zhang S, Lu J, Zhao X, Wu W, Wang H, Wu Q, et al. A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer. Carcinogenesis. 2010 Jul;31(7):1251–8.
Zhang, Shuyu, et al. “A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer.Carcinogenesis, vol. 31, no. 7, July 2010, pp. 1251–58. Pubmed, doi:10.1093/carcin/bgq089.
Zhang S, Lu J, Zhao X, Wu W, Wang H, Wu Q, Chen X, Fan W, Chen H, Wang F, Hu Z, Jin L, Wei Q, Shen H, Huang W, Lu D. A variant in the CHEK2 promoter at a methylation site relieves transcriptional repression and confers reduced risk of lung cancer. Carcinogenesis. 2010 Jul;31(7):1251–1258.

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

July 2010

Volume

31

Issue

7

Start / End Page

1251 / 1258

Location

England

Related Subject Headings

  • Transcription, Genetic
  • Sp1 Transcription Factor
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Middle Aged
  • Male
  • Lung Neoplasms