Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression.
Alterations in DNA methylation have been associated with genome-wide hypomethylation and regional de novo methylation in numerous cancers. De novo methylation is mediated by the de novo methyltransferases Dnmt3a and 3b, but only Dnmt3b has been implicated in promoting cancer by silencing of tumor-suppressor genes. In this study, we have analyzed the role of Dnmt3a in lung cancer by using a conditional mouse tumor model. We show that Dnmt3a deficiency significantly promotes tumor growth and progression but not initiation. Changes in gene expression show that Dnmt3a deficiency affects key steps in cancer progression, such as angiogenesis, cell adhesion, and cell motion, consistent with accelerated and more malignant growth. Our results suggest that Dnmt3a may act like a tumor-suppressor gene in lung tumor progression and may be a critical determinant of lung cancer malignancy.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Qing
Q
Gao
Eveline J
EJ
Steine
M Inmaculada
MI
Barrasa
Dirk
D
Hockemeyer
Mathias
M
Pawlak
Dongdong
D
Fu
Seshamma
S
Reddy
George W
GW
Bell
Rudolf
R
Jaenisch
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers; D004195:Disease Models, Animal; D018450:Disease Progression; D020868:Gene Silencing; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
D017931:DNA Primers; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A