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

Oncogene volume 26, pages 4761–4773 (2007)Cite this article

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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References

  • Adimoolam S, Ford JM . (2002). p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci USA 99: 12985–12990.

    Article  CAS  Google Scholar 

  • Alain S, Giuseppina GM, Simone B, Alain S . (2001). Association between DNA repair-deficiency and high level of p53 mutations in melanoma of xeroderma pigmentosum. Cancer Res 61: 2480–2486.

    Google Scholar 

  • Azzam EI, Nagasawa H, Yu Y, Li CY, Little JB . (2002). Cell cycle deregulation and xeroderma pigmentosum group C cell transformation. J Invest Dermatol 119: 1350–1354.

    Article  CAS  Google Scholar 

  • Bosken CH, Wei Q, Amos CI, Spitz MR . (2002). An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst 94: 1091–1099.

    Article  Google Scholar 

  • Chang MY, Chong IW, Chen FM, Wang JY, Cheng TL, Cheng YJ et al. (2005). High frequency of frameshift mutation on p53 gene in Taiwanese with non small cell lung cancer. Cancer Lett 222: 195–204.

    Article  CAS  Google Scholar 

  • Chang TJ . (2004). An economic and efficient method of RNAi vector constructions. Anal Biochem 334: 199–200.

    Article  CAS  Google Scholar 

  • Cheo DL, Burns DK, Meira LB, Houle JF, Friedberg EC . (1999). Mutational inactivation of the xeroderma pigmentosum group C gene confers predisposition to 2-acetylaminofluorene-induced liver and lung cancer and to spontaneous testicular cancer in Trp53−/− mice. Cancer Res 59: 771–775.

    CAS  PubMed  Google Scholar 

  • Emmert S, Kobayashi N, Khan SG, Kraemer KH . (2000). The xeroderma pigmentosum group C gene leads to selective repair of cyclobutane pyrimidine dimers rather than 6–4 photoproducts. Proc Natl Acad Sci USA 97: 2151–2156.

    Article  CAS  Google Scholar 

  • Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN et al. (2000). Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60: 2368–2371.

    CAS  PubMed  Google Scholar 

  • Friedberg EC . (2001). How nucleotide excision repair protects against cancer. Nat Rev Cancer 1: 22–33.

    Article  CAS  Google Scholar 

  • Gao WM, Mady HH, Yu GY, Siegfried JM, Luketich JD, Melhem MF et al. (2003). Comparison of p53 mutations between adenocarcinoma and squamous cell carcinoma of the lung: unique spectra involving G to A transitions and G to T transversions in both histologic types. Lung Cancer 40: 141–150.

    Article  Google Scholar 

  • Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826.

    Article  CAS  Google Scholar 

  • Hollander MC, Philburn RT, Patterson AD, Velasco-Miguel S, Friedberg EC, Linnoila RI et al. (2005). Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc Natl Acad Sci USA 102: 13200–13205.

    Article  CAS  Google Scholar 

  • Hu Z, Wang Y, Wang X, Liang G, Miao X, Xu Y et al. (2005). DNA repair gene XPC genotypes/haplotypes and risk of lung cancer in a Chinese population. Int J Cancer 115: 478–483.

    Article  CAS  Google Scholar 

  • Inga A, Nahari D, Velasco-Miguel S, Friedberg EC, Resnick MA . (2002). A novel p53 mutational hotspot in skin tumors from UV-irradiated Xpc mutant mice alters transactivation functions. Oncogene 21: 5704–5715.

    Article  CAS  Google Scholar 

  • Janicijevic A, Sugasawa K, Shimizu Y, Hanaoka F, Wijgers N, Djurica M . (2003). DNA bending by the human damage recognition complex XPC-HR23B. DNA Repair (Amst) 2: 325–336.

    Article  CAS  Google Scholar 

  • Kang MS, Lee HJ, Lee JH, Ku JL, Lee KP, Kelley MJ et al. (1996). Mutation of p53 gene in hepatocellular carcinoma cell lines with HBX DNA. Int J Cancer 67: 898–902.

    Article  CAS  Google Scholar 

  • Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC et al. (2001). p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res 61: 3419–3424.

    CAS  PubMed  Google Scholar 

  • Ko JL, Cheng YW, Chang SL, Su JM, Chen CY, Lee H . (2000). MDM2 mRNA expression is a favorable prognostic factor in non-small-cell lung cancer. Int J Cancer 89: 265–270.

    Article  CAS  Google Scholar 

  • Ko JL, Chiao MC, Chang SL, Lin P, Lin JC, Sheu GT et al. (2002). A novel p53 mutant retained functional activity in lung carcinomas. DNA Repair (Amst) 4: 755–762.

    Article  Google Scholar 

  • Le Calvez F, Mukeria A, Hunt JD, Kelm O, Hung RJ, Taniere P et al. (2005). TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 65: 5076–5083.

    Article  CAS  Google Scholar 

  • Marin MS, Lopez-Cima MF, Garcia-Castro L, Pascual T, Marron MG, Tardon A . (2004). Poly (AT) polymorphism in intron 11 of the XPC DNA repair gene enhances the risk of lung cancer. Cancer Epidemiol Biomarkers Prev 13: 1788–1793.

    CAS  PubMed  Google Scholar 

  • Marsit CJ, Karagas MR, Danaee H, Liu M, Andrew A, Schned A et al. (2006). Carcinogen exposure and gene promoter hypermethylation in bladder cancer. Carcinogenesis 27: 112–116.

    Article  CAS  Google Scholar 

  • Matsukura S, Soejima H, Nakagawachi T, Yakushiji H, Ogawa A, Fukuhara M et al. (2003). CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. Br J Cancer 88: 521–529.

    Article  CAS  Google Scholar 

  • Mellon I, Hock T, Reid R, Porter PC, States JC . (2002). Polymorphisms in the human xeroderma pigmentosum group A gene and their impact on cell survival and nucleotide excision repair. DNA Repair (Amst) 1: 531–546.

    Article  CAS  Google Scholar 

  • Nahari D, McDaniel LD, Task LB, Daniel RL, Velasco-Miguel S, Friedberg EC . (2004). Mutations in the Trp53 gene of UV-irradiated Xpc mutant mice suggest a novel Xpc-dependent DNA repair process. DNA Repair (Amst) 3: 379–386.

    Article  CAS  Google Scholar 

  • Neumann AS, Sturgis EM, Wei Q . (2005). Nucleotide excision repair as a marker for susceptibility to tobacco-related cancers: a review of molecular epidemiological studies. Mol Carcinog 42: 65–92.

    Article  CAS  Google Scholar 

  • Nutt CL, Loktionova NA, Pegg AE, Chambers AF, Cairncross JG . (1999). O(6)-methylguanine-DNA methyltransferase activity, p53 gene status and BCNU resistance in mouse astrocytes. Carcinogenesis 20: 2361–2365.

    Article  CAS  Google Scholar 

  • Park JY, Park SH, Choi JE, Lee SY, Jeon HS, Cha SI et al. (2002). Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 11: 993–997.

    CAS  PubMed  Google Scholar 

  • Pavanello S, Pulliero A, Siwinska E, Mielzynska D, Clonfero E . (2005). Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers. Carcinogenesis 26: 169–175.

    Article  CAS  Google Scholar 

  • Piao CQ, Willey JC, Hei TK . (1999). Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential. Carcinogenesis 20: 1529–1533.

    Article  CAS  Google Scholar 

  • Pulling LC, Vuillemenot BR, Hutt JA, Devereux TR, Belinsky SA . (2004). Aberrant promoter hypermethylation of the death-associated protein kinase gene is early and frequent in murine lung tumors induced by cigarette smoke and tobacco carcinogens. Cancer Res 64: 3844–3848.

    Article  CAS  Google Scholar 

  • Reis AM, Cheo DL, Meira LB, Greenblatt MS, Bond JP, Nahari D et al. (2000). Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice. Cancer Res 60: 1571–1579.

    CAS  PubMed  Google Scholar 

  • Riedl T, Hanaoka F, Egly JM . (2003). The comings and goings of nucleotide excision repair factors on damaged DNA. EMBO J 22: 5293–5303.

    Article  CAS  Google Scholar 

  • Ryk C, Kumar R, Sanyal S, Verdier PJ, Hemminki K, Larsson P et al. (2006). Influence of polymorphism in DNA repair and defense genes on p53 mutations in bladder tumours. Cancer Lett 8: 142–149.

    Article  Google Scholar 

  • Sands AT, Abuin A, Sanchez A, Conti CJ, Bradley A . (1995). High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Nature 377: 162–165.

    Article  CAS  Google Scholar 

  • Schagdarsurengin U, Wilkens L, Steinemann D, Flemming P, Kreipe HH, Pfeifer GP et al. (2003). Frequent epigenetic inactivation of the RASSF1A gene in hepatocellular carcinoma. Oncogene 22: 1866–1871.

    Article  CAS  Google Scholar 

  • Shen H, Spitz MR, Qiao Y, Guo Z, Wang LE, Bosken CH et al. (2003). Smoking, DNA repair capacity and risk of non-small cell lung cancer. Int J Cancer 107: 84–88.

    Article  CAS  Google Scholar 

  • Soria JC, Rodriguez M, Liu DD, Lee JJ, Hong WK, Mao L . (2002). Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers. Cancer Res 2: 351–355.

    Google Scholar 

  • Srivenugopal KS, Shou J, Mullapudi SR, Lang Jr FF, Rao JS, Ali-Osman F . (2001). Enforced expression of wild-type p53 curtails the transcription of the O(6)-methylguanine-DNA methyltransferase gene in human tumor cells and enhances their sensitivity to alkylating agents. Clin Cancer Res 7: 1398–1409.

    CAS  PubMed  Google Scholar 

  • Suk R, Gurubhagavatula S, Park S, Zhou W, Su L, Lynch TJ et al. (2005). Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients. Clin Cancer Res 11: 1534–1538.

    Article  CAS  Google Scholar 

  • Tapias A, Auriol J, Forget D, Enzlin JH, Scharer OD, Coin F et al. (2004). Ordered conformational changes in damaged DNA induced by nucleotide excision repair factors. J Biol Chem 279: 19074–19083.

    Article  CAS  Google Scholar 

  • Toyooka S, Maruyama R, Toyooka KO, McLerran D, Feng Z, Fukuyama Y et al. (2003a). Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer 103: 153–160.

    Article  CAS  Google Scholar 

  • Toyooka S, Tsuda T, Gazdar AF . (2003b). The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 21: 229–239.

    Article  CAS  Google Scholar 

  • Vodicka P, Kumar R, Stetina R, Musak L, Soucek P, Haufroid V et al. (2004). Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant. Environ Mol Mutagen 44: 283–292.

    Article  CAS  Google Scholar 

  • Wei Q, Cheng L, Amos CI, Musak L, Soucek P, Haufroid V et al. (2000). Repair oftobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst 92: 1764–1772.

    Article  CAS  Google Scholar 

  • Wolf P, Hu YC, Doffek K, Sidransky D, Ahrendt SA . (2001). O(6)-Methylguanine-DNA methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer. Cancer Res 61: 8113–8117.

    CAS  PubMed  Google Scholar 

  • Wu MF, Cheng YW, Lai JC, Hsu MC, Chen JT, Liu WS et al. (2005). Frequent p16INK4a promoter hypermethylation in human papillomavirus-infected female lung cancer in Taiwan. Int J Cancer 113: 440–445.

    Article  CAS  Google Scholar 

  • Zhang YJ, Chen Y, Ahsan H, Lunn RM, Lee PH, Chen CJ et al. (2003). Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma. Int J Cancer 103: 440–444.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Science Council (NSC94–2314-B-040–024) and the Department of Health (DOH94-TD-G-111–017), the Executive Yuan, Republic of China. We thank Dr Chow, KC, Institute of Biomedical Science, National Chung-Hsing University, for his help to establish the polyclonal antibody of XPC.

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Authors and Affiliations

  1. Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC

    Y-H Wu, J-H Tsai Chang & H Lee

  2. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC

    Y-W Cheng

  3. Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC

    T-C Wu

  4. Lung Cancer Research Center, Chung Shan Medical University, Taichung, Taiwan, ROC

    J-H Tsai Chang, Y-W Cheng, T-C Wu & H Lee

  5. Department of Thoracic Surgery, China Medical University, Taichung, Taiwan, ROC

    C-Y Chen

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Correspondence to H Lee.

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Wu, YH., Tsai Chang, JH., Cheng, YW. et al. Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers. Oncogene 26, 4761–4773 (2007). https://doi.org/10.1038/sj.onc.1210284

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