An essential role for DNA methyltransferase DNMT3B in cancer cell survival.
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 adult tissues. Here we have shown that depletion of DNMT3B, but not DNMT3A, induced apoptosis of human cancer cells but not normal cells. DNMT3B depletion reactivated methylation-silenced gene expression but did not induce global or juxtacentromeric satellite demethylation as did specific depletion of DNMT1. Furthermore, the effect of DNMT3B depletion was rescued by exogenous expression of either of the splice variants DNMT3B2 or DNMT3B3 but not DNMT1. These results indicate that DNMT3B has significant site selectivity that is distinct from DNMT1, regulates aberrant gene silencing, and is essential for cancer cell survival.
Beaulieu
Normand
N
Department of Molecular Biology, MethylGene Inc., Montreal H4S 2A1, Canada.
Morin
Steves
S
Chute
Ian C
IC
Robert
Marie-France
MF
Nguyen
Hannah
H
MacLeod
A Robert
AR
D017209:Apoptosis; D002470:Cell Survival / Q000502:physiology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D004273:DNA, Neoplasm; D000097584:DNA Methyltransferase 3B