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Transcriptional silencing of the Wnt-antagonist DKK1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (2), pp. e30359. Date of Electronic Publication: 2012 Feb 17. - Publication Year :
- 2012
-
Abstract
- The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine activation of canonical Wnt signaling promotes proliferation and dissemination, while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is low or undetectable in a subset of patients with advanced MM as well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt pathway activation, evidenced by nuclear accumulation of β-catenin, which in turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling.
- Subjects :
- Azacitidine pharmacology
Base Sequence
Bone Marrow drug effects
Bone Marrow metabolism
Bone Marrow pathology
Cell Line, Tumor
DNA Methylation drug effects
Disease Progression
Humans
Molecular Sequence Data
Multiple Myeloma pathology
Neoplasm Staging
Wnt Proteins metabolism
Wnt Signaling Pathway drug effects
Wnt Signaling Pathway genetics
DNA Methylation genetics
Gene Silencing drug effects
Intercellular Signaling Peptides and Proteins genetics
Multiple Myeloma genetics
Promoter Regions, Genetic
Transcription, Genetic drug effects
Wnt Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22363428
- Full Text :
- https://doi.org/10.1371/journal.pone.0030359