Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells
Journal
Genome Research
Journal Volume
27
Journal Issue
4
Pages
533-544
Date Issued
2017
Author(s)
Abstract
Reversing DNA methylation abnormalities and associated gene silencing, through inhibiting DNA methyltransferases (DNMTs) is an important potential cancer therapy paradigm. Maximizing this potential requires defining precisely how these enzymes maintain genome-wide, cancer-specific DNA methylation. To date, there is incomplete understanding of precisely how the three DNMTs, 1, 3A, and 3B, interact for maintaining DNA methylation abnormalities in cancer. By combining genetic and shRNA depletion strategies, we define not only a dominant role for DNA methyltransferase 1 (DNMT1) but also distinct roles of 3A and 3B in genome-wide DNA methylation maintenance. Lowering DNMT1 below a threshold level is required for maximal loss of DNA methylation at all genomic regions, including gene body and enhancer regions, and for maximally reversing abnormal promoter DNA hypermethylation and associated gene silencing to reexpress key genes. It is difficult to reach this threshold with patient-Tolerable doses of current DNMT inhibitors (DNMTIs). We show that new approaches, like decreasing the DNMT targeting protein, UHRF1, can augment the DNA demethylation capacities of existing DNA methylation inhibitors for fully realizing their therapeutic potential. ?2017 Cai et al.
SDGs
Other Subjects
DNA methyltransferase 1; DNA methyltransferase 3A; DNA methyltransferase 3B; short hairpin RNA; CCAAT enhancer binding protein; DNA (cytosine 5) methyltransferase 1; DNMT1 protein, human; UHRF1 protein, human; Article; cancer genetics; controlled study; DNA methylation; enhancer region; gene expression; gene silencing; HCT 116 cell line; human; human cell; priority journal; promoter region; protein targeting; gene expression regulation; genetics; human genome; metabolism; CCAAT-Enhancer-Binding Proteins; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Gene Expression Regulation, Neoplastic; Genome, Human; HCT116 Cells; Humans; Promoter Regions, Genetic
Publisher
Cold Spring Harbor Laboratory Press
Type
journal article