Gene promoter hypermethylation in mouse lung tumors.
The mouse is a good model for evaluating the efficacy of chemopreventive agents for lung cancer. Gene silencing by promoter hypermethylation is a critical component for the development and progression of lung cancer and an emerging target for preventive intervention by demethylating agents. Genes methylated in mouse lung tumors could serve as biomarkers to evaluate the effectiveness of demethylating agents for preventing lung cancer and causing gene reexpression in vivo. The purpose of the current study was to evaluate a panel of genes inactivated by promoter hypermethylation in human lung cancer for silencing by this epigenetic mechanism in murine lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), cigarette smoke, or arising spontaneously. Cadherin-13, estrogen receptor-alpha, progesterone receptor, and runt-related transcription factor-3 were frequently methylated in mouse lung tumor-derived cell lines, whereas cadherin-1 and suppressor of cytokine signaling-1 were not. Methylation within these four genes was associated with lack of expression that could be restored after treatment with 5-aza-2'-deoxycytidine and with methylation within the CpG island of each gene. Methylation-specific PCR revealed that methylation of these four genes occurred at prevalences of 24% to 69% in primary lung tumors arising spontaneously or induced by exposure to cigarette smoke or NNK. Estrogen receptor-alpha methylation was more frequent in spontaneously occurring lung cancer than cigarette smoke-induced or NNK-induced lung cancer, whereas runt-related transcription factor-3 showed the opposite relationship. Thus, genes can be targeted for inactivation by methylation, depending on exposure history. This study indicates that methylation events frequently observed in human lung cancer are recapitulated in the mouse model and identifies four potential biomarkers for assessing intervention approaches for reversing epigenetically mediated gene silencing.
Vuillemenot
Brian R
BR
Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108, USA.
Hutt
Julie A
JA
Belinsky
Steven A
SA
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D000077209:Decitabine; D047628:Estrogen Receptor alpha / Q000235:genetics; D020868:Gene Silencing; D052138:Genes, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics; D058125:Transcription Factor 7-Like 1 Protein
D014408:Biomarkers, Tumor; D015820:Cadherins; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; C099972:H-cadherin; D011980:Receptors, Progesterone; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine