Epigenetic gene silencing in cancer.

Abstract

The classical theory of recessive oncogenesis predicted a mutational mechanism for the inactivation of tumor suppressor (TS) genes. This prediction has been amply confirmed, but an alternative, nonmutational, pathway for loss of TS gene activity has also come into focus. For some TS genes, this epigenetic pathway is more frequent than the mutational one. The best-studied DNA modification that correlates with epigenetic gene silencing is methylation of cytosine residues in CpG sequences, and CpG methylation has recently been linked to an even more general mechanism of epigenetic silencing, histone deacetylation. From a combination of descriptive studies and manipulative experiments, some hints of mechanisms for epigenetic silencing of TS genes in cancer cells are beginning to emerge. Here, I discuss several well-documented examples of epigenetic gene silencing in human cancers. I then consider potential mechanisms for de novo methylation of TS genes in cancer. These include spreading of DNA methylation from repetitive sequences into promoterassociated CpG islands secondary to loss of transcriptional activator proteins, gain of methylation secondary to hyperexpression of transcriptional repressors, primary hypermethylation due to hyperexpression of methyltransferases, and interallelic transfer of methylation via gene pairing. In some cancers, environmental pressures that select for a hypermethylating cellular phenotype may drive these processes. DNA methylation and heritable gene silencing Epigenetic gene silencing refers to nonmutational gene inactivation that can be faithfully propagated from precursor cells to clones of daughter cells. The addition of methyl groups to cytosine residues in CpG dinucleotides in DNA is a biochemical modification that meets this requirement. A very striking example of the potential for CpG methylation to be heritable is provided by epimutations in plants. Genes carrying epimutations cause morphological phenotypes to be transmitted from generation to generation, not based on any alteration in the