Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers

Y. H. Wu, J. H. Tsai Chang, Y. W. Cheng, T. C. Wu, C. Y. Chen, H. Lee

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Reduced DNA repair capability is associated with developing lung cancer, especially in nonsmokers. XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process. We hypothesize that inactivation of XPC by promoter hypermethylation may play an important role in the reduction of DNA repair capability to cause p53 mutation during lung carcinogenesis. In this report we demonstrate that hypermethylation of 17 CpG islands between -175 and -1 of the XPC promoter correlates very well with XPC expression levels in eight lung cancer cell lines. When cells with hypermethylated XPC promoters were treated with the demethylating agent 5-aza-2′-deoxycytidine, XPC expression was de-repressed. Interestingly, XPC hypermethylation was found in 4 of 5 (80%) lung cancer cell lines harbored p53 mutation, but not observed in two lung cancer cells which had a wild-type p53 gene. Among the analysis of the hypermethylation status of 158 lung tumors, XPC hypermethylation is more common in nonsmokers (39 of 94, 41%) than in smokers (14 of 64, 22%; P=0.010). Additionally, XPC hypermethylation is more often with G → T or G → C mutations in the p53 gene. To verify whether XPC inactivation is involved in the occurrence of p53 mutation, XPC gene of A549 cells was knockdown by a small interference RNA and then XPC-inactivated cells were treated with benzo[a]pynrene for different passages. Surprisingly, G → T mutation in p53 gene at codon 215 was indeed detected in XPC-inactivated A549 cells of passages 15 and confirmed by loss of transcription activity of mdm2. These results show that hypermethylation of the XPC promoter may play a crucial role in XPC inactivation, which may partly contribute to the occurrence of p53 mutations during lung tumorigenesis, especially nonsmokers.

Original languageEnglish
Pages (from-to)4761-4773
Number of pages13
JournalOncogene
Volume26
Issue number33
DOIs
Publication statusPublished - Jul 19 2007
Externally publishedYes

Fingerprint

Xeroderma Pigmentosum
Lung Neoplasms
Gene Expression
Mutation
p53 Genes
DNA Repair
decitabine
Lung
Carcinogenesis
Cell Line
CpG Islands
RNA Interference
Codon
DNA Damage
DNA
Genes
Neoplasms

Keywords

  • Non-small cell lung cancer
  • p53 mutation
  • Promoter methylation
  • Xeroderma pigmentosum group C (XPC)

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers. / Wu, Y. H.; Tsai Chang, J. H.; Cheng, Y. W.; Wu, T. C.; Chen, C. Y.; Lee, H.

In: Oncogene, Vol. 26, No. 33, 19.07.2007, p. 4761-4773.

Research output: Contribution to journalArticle

Wu, Y. H. ; Tsai Chang, J. H. ; Cheng, Y. W. ; Wu, T. C. ; Chen, C. Y. ; Lee, H. / Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers. In: Oncogene. 2007 ; Vol. 26, No. 33. pp. 4761-4773.
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abstract = "Reduced DNA repair capability is associated with developing lung cancer, especially in nonsmokers. XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process. We hypothesize that inactivation of XPC by promoter hypermethylation may play an important role in the reduction of DNA repair capability to cause p53 mutation during lung carcinogenesis. In this report we demonstrate that hypermethylation of 17 CpG islands between -175 and -1 of the XPC promoter correlates very well with XPC expression levels in eight lung cancer cell lines. When cells with hypermethylated XPC promoters were treated with the demethylating agent 5-aza-2′-deoxycytidine, XPC expression was de-repressed. Interestingly, XPC hypermethylation was found in 4 of 5 (80{\%}) lung cancer cell lines harbored p53 mutation, but not observed in two lung cancer cells which had a wild-type p53 gene. Among the analysis of the hypermethylation status of 158 lung tumors, XPC hypermethylation is more common in nonsmokers (39 of 94, 41{\%}) than in smokers (14 of 64, 22{\%}; P=0.010). Additionally, XPC hypermethylation is more often with G → T or G → C mutations in the p53 gene. To verify whether XPC inactivation is involved in the occurrence of p53 mutation, XPC gene of A549 cells was knockdown by a small interference RNA and then XPC-inactivated cells were treated with benzo[a]pynrene for different passages. Surprisingly, G → T mutation in p53 gene at codon 215 was indeed detected in XPC-inactivated A549 cells of passages 15 and confirmed by loss of transcription activity of mdm2. These results show that hypermethylation of the XPC promoter may play a crucial role in XPC inactivation, which may partly contribute to the occurrence of p53 mutations during lung tumorigenesis, especially nonsmokers.",
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