Epigenetically Active Therapies for Osteosarcoma

摘要

The methylation of cytosine bases occurs post-replication with the addition of a methyl group to the 5 position of the cytosine ring when a cytosine is followed by a guanine (CpG) in sequence. The addition is made by DNA methyltransferases (DNMTs) using the methyl donor s-adenosyl methionine. DNMT1 is responsible for maintenance methylation by which parental strand methylation patterns are copied onto daughter strand CpGs post-replication. DNMT3a is responsible for placing methylation marks on CpGs under conditions of dynamic epigenetic change. Mutations of both proteins have been shown to cause alterations of both global genomic methylation and gene promoter-specific methylation associated with cancer. Methyl groups are removed primarily by removalof the methylated base and repair to cytosine. Oxidation of the methylcytosine to hydroxymethylcytosine, formylcytosine, or carboxylcytosine can result in removal of part or all of the base and repair to unmethylated cytosine. The AID or APOBEC enzymescatalyze deamination of the base. TET enzymes that catalyze conversion to formyl- or carboxylcytosine lead to removal of the adduct and direct restoration of unmethylated cytosine. Across mammalian genomes, CpG dinucleotides are relatively rare sequential base pairs. Sporadically, CpG may be found in high density in regions called CpG islands that are frequently located in association with the 5' control regions of genes. Hypermethylation of these islands was originally thought to result in persistent silencing of the associated gene. New work has demonstrated, however, that chromatin marks on histones are responsible for the active silencing of the gene, which can often be expressed even when methylated. These hypermethylated genes will revert to a silenced state in relatively short order when the signal for the histone changes recedes.1 Recently, a third concept of CpGs has emerged. The CpGs residing in the lower-density regions near CpG islands are considered to reside on the "shores" and "shelves"of those islands and appear to play a significant role in cell development and stem cell function. Put most simply, epigenetic changes like DNA methylation are the mechanism by which cells establish persistent and stable phenotype while sharing a commongenotype across all cells. Certain sets of genes in each cell are mostly permanently turned on or off to limit the set of proteins that are expressed. These mechanisms become labile in the course of carcinogenesis, changing the gene sets available to cancer cells and resulting in significant genetic and epigenetic plasticity. Further, labile somatic cells, including important immune-regulating cells, utilize DNA methylation as a persistent epigenetic mark to modify phenotype during immune reactions andimmune-repressed states. Each of these manifestations of DNA methylation represents a therapeutic target. The approach of using epigenetically active therapy to modify anti-tumor therapy sensitivity, immune response, and modify the metastatic cascade has been minimally explored, but may represent a large, untapped potential in cancer treatment.