DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling

Yuanzi Yu, Wenji Yan, Xuefeng Liu, Yan Jia, Baoping Cao, Yingyan Yu, Youyong Lv, Malcolm V Brock, Jame G. Herman, Julien Licchesi, Yunsheng Yang, Mingzhou Guo

Research output: Contribution to journalArticle

Abstract

Dapper, Dishevelled-associated antagonist of β-catenin (DACT), is a key regulator of Wnt signaling pathway. The purpose of this study is to explore the epigenetic changes and the function of DACT2 in human gastric cancer (GC). Eight human gastric cancer cell lines, 167 cases of primary gastric cancer and 8 cases of normal gastric mucosa were involved in this study. In addition, methylation Specific PCR (MSP), semi-quantitative RT-PCR, colony formation assay, flow cytometry assay, siRNA, immunofluorescence techniques and xenograft mice models were employed. The results indicate that DACT2 is frequently methylated in human primary gastric cancer (55.7%), and that methylation of DACT2 is associated with lost or reduction in its expression (X2 test, P < 0.01). We found that DACT2 expression was regulated by promoter region hypermethylation. Methylation of DACT2 is associated with tumor differentiation, invasion and intravascular cancerous emboli (X2 test, P < 0.05, P < 0.05 and P < 0.05). In gastric cancer patients treated with 5-FU and cisplatin, the five-year survival rates are higher in DACT2 methylated cases. DACT2 inhibits cell proliferation, migration and invasion in gastric cancer cells and suppresses gastric cancer xenografts in mice. Restoration of DACT2 expression inhibits both canonical and noncanonical WNT signaling in SGC7901 cells. Restoration of DACT2 expression sensitized gastric cancer cells to paclitaxel and 5-FU. In conclusion, DACT2 is frequently methylated in human gastric cancer and DACT2 expression is silenced by promoter region hypermethylation. DACT2 suppressed gastric cancer proliferation, invasion and metastasis by inhibiting Wnt signaling both in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)710-724
Number of pages15
JournalAmerican Journal of Cancer Research
Volume4
Issue number6
StatePublished - Jan 1 2014

Keywords

  • Chemo-sensitivity
  • DACT2
  • DNA methylation
  • Gastric cancer
  • Wnt signaling pathway

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Yu, Y., Yan, W., Liu, X., Jia, Y., Cao, B., Yu, Y., Lv, Y., Brock, M. V., Herman, J. G., Licchesi, J., Yang, Y., & Guo, M. (2014). DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling. American Journal of Cancer Research, 4(6), 710-724.