DACT2 is a functional tumor suppressor through inhibiting Wnt/?-catenin pathway
and associated with poor survival in colon cancer
#MMPMID25023701
Wang S
; Dong Y
; Zhang Y
; Wang X
; Xu L
; Yang S
; Li X
; Dong H
; Xu L
; Su L
; Ng SS
; Chang Z
; Sung JJ
; Zhang X
; Yu J
Oncogene
2015[May]; 34
(20
): 2575-85
PMID25023701
show ga
Dapper homolog (DACT) 2 is one of the Dact gene family members, which are
important modulators of Wnt signaling pathway. We aim to clarify its epigenetic
inactivation, biological function and clinical implication in colon cancer. DACT2
was silenced in five out of eight colon cancer cell lines, but robustly expressed
in normal colon tissues. The loss of DACT2 expression was regulated by promoter
hypermethylation. Restoring DACT2 expression in colon cancer cell lines
suppressed tumor cell growth by inducing cell apoptosis and inhibiting cell
proliferation both in vitro and in vivo. Moreover, DACT2 overexpression
effectively reduced lung metastasis of colon cancer cells in nude mice. These
effects by DACT2 were attributed to inhibition of Wnt/?-catenin signaling.
Reexpression of DACT2 significantly suppressed the transcriptional activity of
both wild-type ?-catenin and degradation-resistant form mutant ?-catenin (S33Y).
DACT2 could actively shuttle into and out of nuclei, with its predominant
steady-state localization in the cytoplasm dependent on its nuclear export
signal. Co-immunoprecipitation results indicated that DACT2 strongly associated
?-catenin as well as lymphoid enhancer-binding factor 1 (LEF1) and directly
disrupted the formation of the ?-catenin-LEF1 complex in the nucleus. Whereas in
the cytoplasm, DACT2 restored junctional localization of E-cadherin-?-catenin
complexes and prevented ?-catenin nuclear translocation through direct
interaction with ?-catenin. DACT2 methylation was detected in 43.3% (29/67) of
colon cancer tissues, but none in normal controls. Multivariate analysis revealed
that patients with DACT2 methylation had a significant decrease in overall
survival (P=0.006). Kaplan-Meier survival curves showed that DACT2 methylation
was significantly associated with shortened survival in stage I-III colon cancer
patients. In conclusion, DACT2 acts as a functional tumor suppressor in colon
cancer through inhibiting Wnt/?-catenin signaling. Its methylation at early
stages of colon carcinogenesis is an independent prognostic factor.
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