Investigating the epigenetic effects of a prototype smoke-derived carcinogen in human cells.
Global loss of DNA methylation and locus/gene-specific gain of DNA methylation are two distinct hallmarks of carcinogenesis. Aberrant DNA methylation is implicated in smoking-related lung cancer. In this study, we have comprehensively investigated the modulation of DNA methylation consequent to chronic exposure to a prototype smoke-derived carcinogen, benzo[a]pyrene diol epoxide (B[a]PDE), in genomic regions of significance in lung cancer, in normal human cells. We have used a pulldown assay for enrichment of the CpG methylated fraction of cellular DNA combined with microarray platforms, followed by extensive validation through conventional bisulfite-based analysis. Here, we demonstrate strikingly similar patterns of DNA methylation in non-transformed B[a]PDE-treated cells vs control using high-throughput microarray-based DNA methylation profiling confirmed by conventional bisulfite-based DNA methylation analysis. The absence of aberrant DNA methylation in our model system within a timeframe that precedes cellular transformation suggests that following carcinogen exposure, other as yet unknown factors (secondary to carcinogen treatment) may help initiate global loss of DNA methylation and region-specific gain of DNA methylation, which can, in turn, contribute to lung cancer development. Unveiling the initiating events that cause aberrant DNA methylation in lung cancer has tremendous public health relevance, as it can help define future strategies for early detection and prevention of this highly lethal disease.
Tommasi
Stella
S
Department of Cancer Biology, Beckman Research Institute of the City of Hope National Medical Center, Duarte, California, United States of America.
Kim
Sang-in
SI
Zhong
Xueyan
X
Wu
Xiwei
X
Pfeifer
Gerd P
GP
Besaratinia
Ahmad
A
D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D056426:Genetic Loci / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D012907:Smoking / Q000235:genetics*
D001580:Benzopyrenes; D002273:Carcinogens; C072019:benzo(a)pyrene diolepoxide I