Dysregulated transcriptional and post-translational control of DNA methyltransferases in cancer

Cancer is a leading cause of death worldwide. Aberrant promoter hypermethylation of CpG islands associated with tumor suppressor genes can lead to transcriptional silencing and result in tumorigenesis. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and have been reported to be over-expressed in various cancers. This review highlights the current status of transcriptional and post-translational regulation of the DNMT expression and activity with a focus on dysregulation involved in tumorigenesis. The transcriptional up-regulation of DNMT gene expression can be induced by Ras-c-Jun signaling pathway, Sp1 and Sp3 zinc finger proteins and virus oncoproteins. Transcriptional repression on DNMT genes has also been reported for p53, RB and FOXO3a transcriptional regulators and corepressors. In addition, the low expressions of microRNAs 29 family, 143, 148a and 152 are associated with DNMTs overexpression in various cancers. Several important post-translational modifications including acetylation and phosphorylation have been reported to mediate protein stability and activity of the DNMTs especially DNMT1. In this review, we also discuss drugs targeting DNMT protein expression and activation for therapeutic strategy against cancer.