An Essential Role for DNA Methyltransferase DNMT3B in Cancer Cell Survival*

  title={An Essential Role for DNA Methyltransferase DNMT3B in Cancer Cell Survival*},
  author={Normand Beaulieu and Steves Morin and Ian C Chute and M. F. Robert and Hannah Nguyen and A. Robert Macleod},
  journal={The Journal of Biological Chemistry},
  pages={28176 - 28181}
Abnormal methylation and associated silencing of tumor suppressor genes is a common feature of many types of cancers. The observation of persistent methylation in human cancer cells lacking the maintenance methyltransferase DNMT1 suggests the involvement of other DNA methyltransferases in gene silencing in cancer. To test this hypothesis, we have evaluated methylation and gene expression in cancer cells specifically depleted of DNMT3A or DNMT3B,de novo methyltransferases that are expressed in… 

Figures from this paper

Antiproliferative Effects of DNA Methyltransferase 3B Depletion Are Not Associated with DNA Demethylation
The results show that DNMT3B is dispensable for the maintenance of aberrant DNA methylation patterns in human colon cancer cells and they have important implications for the development of targeted DNA methyltransferase inhibitors as epigenetic cancer drugs.
DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells
Results indicate that DNMT1 is necessary and sufficient to maintain global methylation and aberrant CpG island methylation in human cancer cells.
Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas
Effects of increased presence of DNMTs on inhibition of tumor suppressors that are epigenetically silenced in gliomas, thereby leading to aberrant regulation of cell cycle progression and failure to maintain genomic stability are identified.
Global identification of genes targeted by DNMT3b for epigenetic silencing in lung cancer
A key role for DNMT3b is identified in the earliest stages of initiation and a comprehensive catalog of genes targeted for silencing by this methyltransferase in non-small-cell lung cancer is provided.
Depletion of DNMT3A Suppressed Cell Proliferation and Restored PTEN in Hepatocellular Carcinoma Cell
Insight is provided into the mechanisms of DNMT3A to regulate TSGs by an epigenetic approach in HCC and Demethylation of PTEN promoter was observed in DNMT2A-depleted cells implying that DN MT3A silenced PTEN via DNA methylation.
Down-regulation of DNMT3b in PC3 cells effects locus-specific DNA methylation, and represses cellular growth and migration
It is demonstrated that DNMT3b depletion results in increased apoptosis and reduced migration of PC3 cells compared to the untransfected control cells and that its depletion significantly reduces growth and migration ofPC3 cells.
The role of DNA methylation in cancer development.
Identification of aberrations of DNA methylation in cancer cells is a new field of investigation in carcinogenesis and it is believed that epigenetic cancer diagnostic and therapy will be achieved in the next decades.
Targeting DNA methylation in cancer
  • M. Szyf
  • Biology
    Ageing Research Reviews
  • 2003
Methyltransferases in apoptosis and cancer
DNA methyltransferases are one of the major candidates linking alterations in chromatin structure, methyltransferase expression and apoptotic cell death in human neoplasia and inactivation of DNMTs using specific inhibitors or antisense strategies is only of limited clinical efficacy.


DNMT1 and DNMT3b cooperate to silence genes in human cancer cells
It is demonstrated that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and compelling evidence that such methylation is essential for optimal neoplastic proliferation is provided.
CpG methylation is maintained in human cancer cells lacking DNMT1
It is shown that cells lacking DNMT1 exhibited markedly decreased cellular DNA methyltransferase activity, but there was only a 20% decrease in overall genomic methylation, indicating thatDNMT1 has an unsuspected degree of regional specificity in human cells and that methylating activities other than DN MT1 can maintain the methylation of most of the genome.
The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors.
Investigation of the expression of human DNMT1, 3a and 3b found widespread, coordinate expression of all three transcripts in most normal tissues, and several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue-specific manner.
Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells.
Analysis of the expression of the mRNAs for DNMT1, 3a and 3b during the cell cycle of normal and transformed cells revealed a new level of control exerted over the cellular DNA methylation machinery, the loss of which provides an alternative mechanism for the genesis of the aberrant methylation patterns observed in tumor cells.
Dnmt3a and Dnmt3b Are Transcriptional Repressors That Exhibit Unique Localization Properties to Heterochromatin*
It is demonstrated that the recently identified DNA methyltransferases, DnMT3a and Dnmt3b, like DNMT1, repress transcription in a methylation-independent manner and are important to the fact that mutations in DNMT3B are found in the developmental syndrome, ICF (immunodeficiency, centromeric heterochromatin instability, and facial anomalies).
DNA methyltransferase expression and DNA methylation of CPG islands and peri‐centromeric satellite regions in human colorectal and stomach cancers
Both over‐expression of the maintenance DNA methyltransferase DNMT1 and over-expression of a newly identified de novo DNA methyl transferase, DNMT3b, are involved in human carcinogenesis, probably at different stages and through different mechanisms.
The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.
The first example of naturally occurring mutations in a mammalian DNA methyltransferase gene is described, occurring in patients with a rare autosomal recessive disorder, termed the ICF syndrome, for immunodeficiency, centromeric instability, and facial anomalies.
Down-regulation of Human DNA-(Cytosine-5) Methyltransferase Induces Cell Cycle Regulators p16 ink4A and p21WAF/Cip1 by Distinct Mechanisms*
The results suggest that the elevated levels of DNA MeTase seen in cancer cells can inhibit tumor suppressors by distinct mechanisms involving either transcriptional inactivation through DNA methylation or by a methylation independent regulation.