Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling

Samuel, Michael S., Suzuki, Hiromu, Buchert, Michael, Putoczki, Tracy L., Tebbutt, Niall C., Lundgren-May, Therese, Christou, Aliki, Inglese, Melissa, Toyota, Minoru, Heath, Joan K., Ward, Robyn L., Waring, Paul M. and Ernst, Matthias (2009) Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling. Gastroenterology, 137 3: 902-913. doi:10.1053/j.gastro.2009.05.042


Author Samuel, Michael S.
Suzuki, Hiromu
Buchert, Michael
Putoczki, Tracy L.
Tebbutt, Niall C.
Lundgren-May, Therese
Christou, Aliki
Inglese, Melissa
Toyota, Minoru
Heath, Joan K.
Ward, Robyn L.
Waring, Paul M.
Ernst, Matthias
Title Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling
Formatted title
Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling
Journal name Gastroenterology   Check publisher's open access policy
ISSN 0016-5085
1528-0012
Publication date 2009-09-01
Sub-type Article (original research)
DOI 10.1053/j.gastro.2009.05.042
Open Access Status Not Open Access
Volume 137
Issue 3
Start page 902
End page 913
Total pages 12
Place of publication Maryland Heights, MO United States
Publisher W.B. Saunders
Collection year 2016
Language eng
Formatted abstract
Background & Aims

Aberrant DNA methylation is a common early event in neoplasia, but it is unclear how this relates to dysregulation of DNA (cytosine-5) methyltransferases (Dnmts). Here we use knock-in transgenic mice to investigate the consequences of intestinal epithelium-specific overexpression of de novo Dnmt3a.

Methods

A novel gene targeting strategy, based on the intestinal epithelium-specific, uniform expression of the A33 glycoprotein, is employed to restrict Dnmt3a overexpression in homozygous A33Dnmt3a mutant mice.

Results

A33Dnmt3a mice infrequently develop spontaneous intestinal polyps. However, when genetically challenged, tumor multiplicity in A33Dnmt3a;ApcMin compound mice is 3-fold higher than in ApcMin mice. Although we observe a requirement for spontaneous loss of heterozygosity of the adenomatous polyposis coli (Apc) gene to trigger tumorigenesis in ApcMin mice, lesions in A33Dnmt3a;ApcMin mice frequently retain the wild-type Apc allele. However, epithelia from normal mucosa and polyps of A33Dnmt3a;ApcMin mice show hypermethylation-mediated transcriptional silencing of the Wnt antagonists Sfrp5, and to a lesser extent, Sfrp1 and increased nuclear β-catenin alongside activation of the Wnt-target gene Axin2/Conductin. Conversely, enforced Sfrp5 expression suppresses canonical Wnt-signaling more effectively in wild-type than in ApcMin cells.

Conclusions

Aberrant activation of the canonical Wnt pathway, either by mono-allelic Apc loss or transcriptional silencing of Sfrp5 is largely insufficient to promote polyposis, but epistatic interactions between these genetic and epigenetic events enables initiation and promotion of disease. This mechanism is likely to play a role in human colorectal cancer, because we also show that elevated DNMT3A expression coincides with repressed SFRP5 and enhanced AXIN2/CONDUCTIN expression in paired patient biopsies.
Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collection: Office of the Vice-Chancellor
 
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Created: Wed, 11 Feb 2015, 10:10:58 EST by Ms Kate Rowe on behalf of Office of the Vice-Chancellor