DNA methylation: an epigenetic pathway to cancer and a promising target for anticancer therapy.
The unique properties of a cancer cell are acquired through a stepwise accumulation of heritable changes in the information content of proto-oncogenes and tumor suppressor genes. While gain, loss, and mutation of genetic information have long been known to contribute to tumorigenesis, it has been increasingly recognized over the past 5 years that 'epigenetic' mechanisms may play an equally important role. The main epigenetic modification of the human genome is methylation of cytosine residues within the context of the CpG dinucleotide. De novo methylation of 'CpG islands' in the promoter regions of tumor suppressor genes may lead to transcriptional silencing through a complex process involving histone deacetylation and chromatin condensation, and thus represents a tumorigenic event that is functionally equivalent to genetic changes like mutation and deletion. DNA methylation is interesting from a diagnostic viewpoint because it may be easily detected in DNA released from neoplastic and preneoplastic lesions into serum, urine or sputum, and from a therapeutic viewpoint because epigenetically silenced genes may be reactivated by inhibitors of DNA methylation and/or histone deacetylase. A better understanding of epigenetic mechanisms leading to tumor formation and chemoresistance may eventually improve current cancer treatment regimens and be instructive for a more rational use of anticancer agents.
Worm
Jesper
J
Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Guldberg
Per
P
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002843:Chromatin / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006657:Histones / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002843:Chromatin; D004273:DNA, Neoplasm; D006657:Histones; D003596:Cytosine; D015254:DNA Modification Methylases