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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/β-catenin signaling. Reexpression of DACT2 significantly suppressed the transcriptional activity of both wild-type β-catenin and degradation-resistant form mutant β-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 β-catenin as well as lymphoid enhancer-binding factor 1 (LEF1) and directly disrupted the formation of the β-catenin-LEF1 complex in the nucleus. Whereas in the cytoplasm, DACT2 restored junctional localization of E-cadherin-β-catenin complexes and prevented β-catenin nuclear translocation through direct interaction with β-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/β-catenin signaling. Its methylation at early stages of colon carcinogenesis is an independent prognostic factor. [ABSTRACT FROM AUTHOR]

SIPA1 (signal-induced proliferation-associated protein 1) is a GTPase activation protein that can catalyze the hydrolysis of Rap1 bound GTP to GDP. Recently attention has been paid to a potential role for SIPA1 in cancer metastasis; however, the underlying mechanism of how changes in SIPA1 levels may lead to increased metastasis remains poorly understood. In this study, we showed that SIPA1 was mainly localized to the nuclei in highly invasive breast cancer tumor tissue and MDA-MB-231 cells. Knockdown of SIPA1 in MDA-MB-231 altered cell morphology and cell proliferation ability. Furthermore, this study is the first to establish that nuclear SIPA1 can interact with the integrin β1 promoter and activate its transcription; this interaction appears to be important for SIPA1-dependent MDA-MB-231 cell adhesion and invasion. We also demonstrated that the phosphorylation of FAK, Akt and the expression of MMP9, downstream signaling molecules of integrin β1, were decreased upon SIPA1 knockdown, and MDA-MB-231 cell invasion was impaired. Taken together, these results suggest nuclear SIPA1 contributes to breast cancer cell invasion through the regulation of integrin β1 signaling. [ABSTRACT FROM AUTHOR]