DNA Methyltransferases: A Novel Target for Prevention and Therapy

Abstract

Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.

High expression of DNA methyltransferases in primary human medulloblastoma

“…Theoretically, inhibition of DNA methylation is a therapeutic opportunity by reversing gene silencing [9,12,14,38]. An in vitro experiment showed that the DNMT inhibitor 5-aza-2'-deoxycytidine (decitabine) reactivates the tumor suppressor PTCH1 gene in the MB cell line [4].…”

“…DNMT1 is responsible for maintenance of methylation patterns during DNA replication. DNMT3A and DNMT3B are regarded as de novo methyl-transferases and abundantly expressed during embryonic development [2,9,14,19,22,28,38].…”

“…Overexpression of DNMTs was detected at the mRNA or protein level. Increased DNMT1 expression was described in gastric cancers, along with DNMT3A in breast and pancreatic cancer, or along with DNMT3B in glioma [8,16,30,38,39]. Although there is emerging evidence that epigenetic events play a remarkable role in the development of adult cancers, our knowledge about their role in pediatric brain tumors is still very limited.…”

“…Therefore, repetitive elements are hypomethylated and specific tumor suppressor genes are repressed due to hypermethylation. These may contribute to chromosomal instability and abnormal gene silencing that could promote tumor-initializing steps [2,9,14,28,38]. Promoter hypermethylation of tumor suppressor genes and DNA repair genes has been observed in a wide variety of tumors, such as colorectal, breast cancer, glioma and medulloblastoma [19,22,36].…”

DNA methyltransferase inhibitors influence on the DIRAS3 and STAT3 expression and in vitro migration of ovarian and breast cancer cells

“…DNA methylation is catalyzed by methyltransferases (DNMT1, DNMT3A, DNMT3B, and DNMT3L) which are responsible for the addition of a methyl group to the carbon-5 position of the cytosine pyrimidine ring in the 5'-CpG-3' dinucleotide. DNMT1 is involved in the maintenance of methylation ensuring merely the methylation pattern fidelity of replicated daughter strands, whereas DNMT3 is a de novo methyltransferase [2].…”