Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a
Aberrant de novo methylation of DNA is considered an important mediator of tumorigenesis. To investigate the role of de novo DNA methyltransferase 3a (Dnmt3a) in intestinal tumor development, we analyzed the expression of Dnmt3a in murine colon crypts, murine colon adenomas and human colorectal canc...
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Published in | Oncogene Vol. 34; no. 14; pp. 1822 - 1830 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
02.04.2015
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Aberrant
de novo
methylation of DNA is considered an important mediator of tumorigenesis. To investigate the role of
de novo
DNA methyltransferase 3a (Dnmt3a) in intestinal tumor development, we analyzed the expression of Dnmt3a in murine colon crypts, murine colon adenomas and human colorectal cancer using RNA fluorescence
in situ
hybridization (FISH), quantitative PCR and immunostaining. Following conditional deletion of
Dnmt3a
in the colon of APC
(Min/+)
mice, we analyzed tumor numbers, genotype of macroadenomas and laser dissected microadenomas, global and regional DNA methylation and gene expression. Our results showed increased Dnmt3a expression in colon adenomas of APC
(Min/+)
mice and human colorectal cancer samples when compared with control tissue. Interestingly, in tumor tissue, RNA FISH analysis showed highest Dnmt3a expression in Lgr5-positive stem/progenitor cells. Deletion of
Dnmt3a
in APC
(Min/+)
mice reduced colon tumor numbers by ~40%. Remaining adenomas and microadenomas almost exclusively contained the non-recombined
Dnmt3a
allele; no tumors composed of the inactivated
Dnmt3a
allele were detected. DNA methylation was reduced at the Oct4, Nanog, Tff2 and Cdkn1c promoters and expression of the tumor-suppressor genes
Tff2
and
Cdkn1c
was increased. In conclusion, our results show that Dnmt3a is predominantly expressed in the stem/progenitor cell compartment of tumors and that deletion of
Dnmt3a
inhibits the earliest stages of intestinal tumor development. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2014.114 |