Open AccessEpigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells
Author(s) -
Xiang Tingxiu,
Li Lili,
Yin Xuedong,
Zhong Lan,
Peng Weiyan,
Qiu Zhu,
Ren Guosheng,
Tao Qian
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12099
Subject(s) - wnt signaling pathway , cancer research , carcinogenesis , biology , ectopic expression , dna methylation , apoptosis , breast cancer , gene silencing , cell , cell growth , microbiology and biotechnology , signal transduction , cancer , cell culture , gene expression , genetics , gene
Dickkopf‐related protein 3 ( DKK 3) is an antagonist of Wnt ligand activity. Reduced DKK 3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK 3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK 3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK 3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK 3 in breast cancer. Ectopic expression of DKK 3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK 3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition ( EMT ) and down‐regulating stem cell markers. DKK 3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK 3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.