Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing of XXXX and EPHB @entity5 suppressor genes in @entity14 .

@entity1 @entity5 @entity189 @entity22166 @entity3546 @entity25335 @entity30411 @entity14 @entity652 @entity23597
Aberrant Wnt/ @entity3546 signaling is a driving force during initiation and progression of @entity14 . Yet, the Wnt/ @entity3546 targets @entity30411 , @entity22166 , @entity23597 and @entity25335 ( @entity25335 ) act as @entity5 suppressors in intestinal epithelial cells and frequently appear to be transcriptionally silenced in @entity189 . The molecular mechanisms which underlie the apparent loss of expression of a subset of Wnt/ @entity3546 targets in a background of persistent pathway activity are largely unknown. To gain insight into this, we quantified expression of @entity30411 and @entity25335 in @entity1 tissue specimens of case-matched colorectal normal mucosa, @entity652 and @entity189 . In particular @entity25335 display biphasic, albeit not strictly coincident, expression profiles with elevated levels in @entity652 and decreased transcription in approximately 30% of the corresponding @entity189 . Consistent with their divergent and variable expression we observed considerable heterogeneity among the epigenetic landscapes at @entity30411 and @entity25335 in a model of @entity14 cell lines. Unlike the inactive @entity30411 locus, @entity25335 maintain DNA hypomethylation of their promoter regions in the silent state. A strong reduction of active histone modifications consistently parallels reduced expression of @entity30411 and @entity23597 and to some extent of @entity22166 . Accordingly, treatment with inhibitors for DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) restored @entity30411 and @entity25335 expression depending upon epigenetic features at their promoters but also upon cellular background. Overall our findings show that downregulation of @entity30411 and EphB receptor genes occurs independently and that different branches of epigenetic control systems including class I and III HDACs contribute to epigenetic silencing of Wnt/ @entity3546 targets during colorectal tumorigenesis.
