PMID- 24837369
OWN - NLM
STAT- MEDLINE
DCOM- 20150615
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 14
DP  - 2015 Apr 2
TI  - Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 
      3a.
PG  - 1822-30
LID - 10.1038/onc.2014.114 [doi]
AB  - 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.
FAU - Weis, B
AU  - Weis B
AD  - Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Schmidt, J
AU  - Schmidt J
AD  - Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Maamar, H
AU  - Maamar H
AD  - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Raj, A
AU  - Raj A
AD  - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Lin, H
AU  - Lin H
AD  - Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical 
      School, Boston, MA, USA.
FAU - Toth, C
AU  - Toth C
AD  - 1] Department of Pathology, University of Heidelberg, National Center for Tumor 
      Diseases (NCT) Tissue Bank, Heidelberg, Germany [2] Department of Pathology, 
      Heinrich Heine University, Dusseldorf, Germany.
FAU - Riedmann, K
AU  - Riedmann K
AD  - Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Raddatz, G
AU  - Raddatz G
AD  - Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Seitz, H-K
AU  - Seitz HK
AD  - Department of Medicine, Salem Medical Center, Alcohol Research Center, University 
      of Heidelberg, Heidelberg, Germany.
FAU - Ho, A D
AU  - Ho AD
AD  - Department of Hematology/Oncology, University of Heidelberg Medical Center, 
      Heidelberg, Germany.
FAU - Lyko, F
AU  - Lyko F
AD  - Division of Epigenetics (A130), German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Linhart, H G
AU  - Linhart HG
AD  - 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.
LA  - eng
GR  - 1DP2OD008514-01/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140519
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Cdkn1c protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p57)
RN  - 0 (DNMT3A protein, human)
RN  - 0 (Dnmt3a protein, mouse)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Mucins)
RN  - 0 (Muscle Proteins)
RN  - 0 (Nanog Homeobox Protein)
RN  - 0 (Nanog protein, mouse)
RN  - 0 (Octamer Transcription Factor-3)
RN  - 0 (Peptides)
RN  - 0 (Pou5f1 protein, mouse)
RN  - 0 (TFF2 protein, human)
RN  - 0 (TFF2 protein, mouse)
RN  - 0 (Trefoil Factor-2)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
SB  - IM
MH  - Adenoma/*genetics/pathology
MH  - Animals
MH  - Cell Transformation, Neoplastic/genetics
MH  - Colon/metabolism/pathology
MH  - Colorectal Neoplasms/*genetics/pathology
MH  - Cyclin-Dependent Kinase Inhibitor p57/biosynthesis/genetics
MH  - DNA (Cytosine-5-)-Methyltransferases/biosynthesis/*genetics
MH  - DNA Methylation/*genetics
MH  - DNA Methyltransferase 3A
MH  - Gene Expression Regulation, Neoplastic
MH  - Homeodomain Proteins/genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mucins/biosynthesis/genetics
MH  - Muscle Proteins/biosynthesis/genetics
MH  - Nanog Homeobox Protein
MH  - Neoplastic Stem Cells/*pathology
MH  - Octamer Transcription Factor-3/genetics
MH  - Peptides/genetics
MH  - Promoter Regions, Genetic
MH  - Real-Time Polymerase Chain Reaction
MH  - Trefoil Factor-2
EDAT- 2014/05/20 06:00
MHDA- 2015/06/16 06:00
CRDT- 2014/05/20 06:00
PHST- 2013/10/22 00:00 [received]
PHST- 2014/03/13 00:00 [revised]
PHST- 2014/03/26 00:00 [accepted]
PHST- 2014/05/20 06:00 [entrez]
PHST- 2014/05/20 06:00 [pubmed]
PHST- 2015/06/16 06:00 [medline]
AID - onc2014114 [pii]
AID - 10.1038/onc.2014.114 [doi]
PST - ppublish
SO  - Oncogene. 2015 Apr 2;34(14):1822-30. doi: 10.1038/onc.2014.114. Epub 2014 May 19.