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PMID: 25023701 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

DACT2 is a functional tumor suppressor through inhibiting Wnt/β-catenin pathway and associated with poor survival in colon cancer.

Oncogene ·Vol. 34 ·No. 20 ·2015-05-14 ·Pages 2575-85

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

Abstract

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.

MeSH Terms
Active Transport, Cell Nucleus/genetics Adaptor Proteins, Signal Transducing Adult Aged Aged, 80 and over Amino Acid Substitution Animals Caco-2 Cells Cadherins/genetics,metabolism Carrier Proteins/genetics,metabolism Cell Nucleus/metabolism,pathology Colonic Neoplasms/genetics,metabolism,mortality,pathology Disease-Free Survival Gene Expression Regulation, Neoplastic HEK293 Cells Humans Lymphoid Enhancer-Binding Factor 1/metabolism Mice Mice, Inbred BALB C Mice, Nude Middle Aged Mutation, Missense Neoplasm Proteins/genetics,metabolism Nuclear Localization Signals/genetics,metabolism Survival Rate Tumor Suppressor Proteins/genetics,metabolism Wnt Signaling Pathway beta Catenin/genetics,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Cadherins Carrier Proteins DACT2 protein, human LEF1 protein, human Lymphoid Enhancer-Binding Factor 1 Neoplasm Proteins Nuclear Localization Signals Tumor Suppressor Proteins beta Catenin
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Wang S
1] Research Center for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China [2] Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Dong Y
1] Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China [2] Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
Zhang Y
School of Medicine, School of Life Sciences, State Key Laboratory of Biomembrane and Membrane Biotechnology, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, China.
Wang X
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Xu L
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Yang S
School of Medicine, School of Life Sciences, State Key Laboratory of Biomembrane and Membrane Biotechnology, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, China.
Li X
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Dong H
Research Center for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China.
Xu L
Research Center for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China.
Su L
Research Center for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China.
Ng S S M
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
Chang Z
School of Medicine, School of Life Sciences, State Key Laboratory of Biomembrane and Membrane Biotechnology, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, China.
Sung J J
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Zhang X
Research Center for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China.
Yu J
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2014.201
Published
2015-05-14
Epub
2014-00-14
Pages
2575-85
Language
English
Region
England
NLM ID
8711562
PMCID
PMC4761644
Subset
IM
External Links
PubMed source DOI: 10.1038/onc.2014.201 PMC Full Text View journal details
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