TY - JOUR
T1 - Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells
AU - Cai, Yi
AU - Tsai, Hsing Chen
AU - Yen, Ray Whay Chiu
AU - Zhang, Yang
AU - Kong, Xiangqian
AU - Wang, Wei
AU - Xia, Limin
AU - Baylin, Stephen B.
N1 - Funding Information:
Research reported in this publication was supported by National Institutes of Environmental Health Sciences under award number R01ES011858, MDxHealth, Hodson Trust, and Samuel Waxman Cancer Research Foundation to S.B.B. and the Ministry of Science and Technology of Taiwan grant MOST 105-2628-B-002- 040-MY3 to H.-C.T. We wish to thank Kathy Bender for manuscript preparation.
Publisher Copyright:
©2017 Cai et al.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.208108.116
DO - 10.1101/gr.208108.116
M3 - Article
C2 - 28232479
AN - SCOPUS:85017556888
VL - 27
SP - 533
EP - 544
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 4
ER -