Format

Send to

Choose Destination
Oncogene. 2015 Apr 2;34(14):1822-30. doi: 10.1038/onc.2014.114. Epub 2014 May 19.

Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a.

Author information

1
Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
4
1] Department of Pathology, University of Heidelberg, National Center for Tumor Diseases (NCT) Tissue Bank, Heidelberg, Germany [2] Department of Pathology, Heinrich Heine University, Düsseldorf, Germany.
5
Department of Medicine, Salem Medical Center, Alcohol Research Center, University of Heidelberg, Heidelberg, Germany.
6
Department of Hematology/Oncology, University of Heidelberg Medical Center, Heidelberg, Germany.
7
1] Department of Medicine, Salem Medical Center, Alcohol Research Center, University of Heidelberg, Heidelberg, Germany [2] Department of Hematology/Oncology, University of Heidelberg Medical Center, Heidelberg, Germany [3] Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

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.

PMID:
24837369
DOI:
10.1038/onc.2014.114
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center