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

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 À175 and À1 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 0 -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 ¼ 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 XPCinactivated 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.

p53 Dysfunction by Xeroderma Pigmentosum Group C Defects Enhance Lung Adenocarcinoma Metastasis via Increased Mmp1 Expression

“…Therefore, XPC defects, combined with the inactivated p53 pathway, may initiate lung adenocarcinoma development. Our previous report indicated that XPC was predominantly affected by promoter hypermethylation and that it may contribute to the occurrence of p53 mutation in lung tumors (5). We also observed XPC defects to be more common in nonsmokers and in early-stage tumors and that XPC mRNA altered by XPC hypermethylation may confer nodal metastasis and tumor recurrence.…”

Spectrophotometric Determination of Nifedipine and Nicardipine in their Pharmaceutical Preparations

“…Our results are supported by a recent study in which the authors did not find any methylation in XPC gene in NSCLC [16]. Contrary to these findings, hypermethylation of XPC gene has been observed in patients with lung and bladder cancer [11][12][13][14][15][16][17]. These discrepant results may be attributed to differences in ethnicity or clinic-pathological features of samples tested in each study.…”

XPC polymorphisms play a role in tissue-specific carcinogenesis: a meta-analysis

“…For lung cancers, there is evidence for XPC promoter hypermethylation, leading to decreased transcription levels of the gene in the early events of carcinogenesis. 69 Depletion of the XPC gene also led to lung tumors in mice, pointing to the importance of this gene for lung carcinogenesis. 8 More recently, the involvement of XPC in photocarcinogenesis was suggested by experiments using XPC/CDKN2a double knockout mice.…”