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|Isofistularin-3 is a direct, DNA-competitive DNMT1 inhibitor, with an IC50 of 13.5 μM. Isofistularin-3, as a DNA demethylating agent, induces cell cycle arrest and sensitization to TRAIL in cancer cel...||Inquiry|
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Fig. 1 DNA methylation pattern in normal and cancer cells (Seminars in Cancer Biology, 2021).
DNA methylation is a critical epigenetic modification that is established and maintained across the genome by DNA methyltransferase enzymes (DNMTs). Among them, DNMT1 plays an important role in the inheritance of genomic DNA methylation. It is coupled to the DNA replication process and is also a therapeutic target for chemotherapy and chemoprevention. DNMT1 is required for faithful maintenance of DNA methylation patterns, as well as aberrant silencing of tumor suppressor genes in human cancer cells essential for their cell cycle progression, proliferation and survival. DNA methylation is reversible and it thus represents an attractive epigenetic target for cancer treatment. DNMT1 is involved in tumorigenesis of several cancer types including hematological cancers (leukemias and lymphomas) and multiple solid tumors (breast, liver, gastric, bone).
Altered patterns of DNA methylation are a frequent occurrence in many tumor genomes, and inhibitors of DNMTs have become important epigenetic drugs. The mammalian DNMT family includes three major members that have functional methylation activities, termed DNMT1, DNMT3A, and DNMT3B. DNMT3A and DNMT3B are responsible for methylation establishment, whereas DNMT1 maintains methylation during DNA replication. DNMT1 preferentially binds to hemimethylated CpG dinucleotides rather than unmethylated counterparts. DNMT1 methylates nascently synthesized CpGs opposite of methylated DNA on the mother strand during S phase, maintaining the methylation inheritance. In addition to its methylation activity, DNMT1 is known to play a role in the DNA-damage response. Compelling evidence from B cell differentiation and induced DNA-damage studies strongly suggest that DNMT1 can act as a genome guardian and an early responder to DNA double-stranded breaks (DSBs) in both B cells and colon cancer cell lines, independently of its catalytic activity. After microirradiation, DNMT1 is rapidly but transiently recruited to DSBs by interacting with proliferating cell nuclear antigen (PCNA) and ATR effector kinase CHK1. Interestingly, DNMT1 has been shown to inhibit aberrant activation of the DNA damage response without exogenous damage.
Fig. 2 Structure of the known DNA methyltransferases (DNMT’s) and DNMT-like proteins (Seminars in Cancer Biology, 2021).
Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation-induced oncogene activation and chromosomal instability. The ectopic expression of DNMT1 can transforms mammalian cells, and the inhibition of DNMT1 activity reverses that phenotypic transformation. Therefore, DNMT1 is considered to be an excellent target for therapeutic intervention. Transfection of DNMT1 siRNA decreased DNMT1 protein levels specifically and effectively. This decrease was accompanied by suppression of cell proliferation and colony-forming ability. The mechanism of this inhibition may be related to the increased levels of the cyclin dependent kinase inhibitor p21. These results suggest that the siRNA approach can be used to disrupt effectively DNMT1 activity and cancer cell growth. The brominated alkaloid Isofistularin-3 (Iso-3), from the marine sponge Aplysina aerophoba, is a new DNA methyltransferase (DNMT)1 inhibitor.