Epigenetic and transcriptional dysregulation of VWA2 associated with a MYC-driven
oncogenic program in colorectal cancer
#MMPMID30038405
González B
; Fece de la Cruz F
; Samuelsson JK
; Alibés A
; Alonso S
Sci Rep
2018[Jul]; 8
(1
): 11097
PMID30038405
show ga
VWA2 encodes AMACO, a secreted protein up-regulated in most colorectal carcinomas
(CRC), constituting a promising biomarker. The mechanism responsible for its
aberrant up-regulation has not been previously described. In this work, we
analyzed VWA2 DNA methylation in over 400 primary CRCs. No epigenetic alterations
were found in its promoter-associated CpG island. However, the region located
downstream of the transcriptional start site was hypomethylated in most CRCs.
ChIP-Seq revealed increased levels of the active mark H3K4me3 and reduction of
the repressive mark H3K27me3. In contrast, several CRC cell lines exhibited
hypermethylation of VWA2. 5-AZA-2-deoxycitidine treatment led to transcriptional
activation of VWA2, supporting a functional link between DNA methylation and
transcription. VWA2 expression in primary CRCs correlated with that of Myc and
Myc-target genes. Transcriptional up-regulation of VWA2 is extremely frequent
(78%) and strong (average fold change >15) in CRC, but not in other types of
cancer. VWA2 undergoes hypomethylation in the majority of CRCs. This alteration
could partly underlie the previously reported over-expression of AMACO.
Co-expression profiling suggests that VWA2 might be a constituent of a larger
oncogenic transcriptional program regulated by c-Myc. Up-regulation of VWA2 is
virtually exclusive of CRC, reinforcing its potential as a specific biomarker.
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