title: Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells.
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.
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University, Taipei, 10051, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10002, Taiwan.
authors.forename: Hsing-Chen
authors.initials: HC
authors.lastname: Tsai
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Ray-Whay Chiu
authors.initials: RC
authors.lastname: Yen
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Yang W
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases