Oncogenic Function of <em>DACT1</em> in Colon Cancer through the Regulation of β-catenin

The Wnt/β-catenin signaling pathway plays important roles in the progression of colon cancer. DACT1 has been identified as a modulator of Wnt signaling through its interaction with Dishevelled (Dvl), a central mediator of both the canonical and noncanonical Wnt pathways. However, the functions of DACT1 in the WNT/β-catenin signaling pathway remain unclear. Here, we present evidence that DACT1 is an important positive regulator in colon cancer through regulating the stability and sublocation of β-catenin. We have shown that DACT1 promotes cancer cell proliferation in vitro and tumor growth in vivo and enhances the migratory and invasive potential of colon cancer cells. Furthermore, the higher expression of DACT1 not only increases the nuclear and cytoplasmic fractions of β-catenin, but also increases its membrane-associated fraction. The overexpression of DACT1 leads to the increased accumulation of nonphosphorylated β-catenin in the cytoplasm and particularly in the nuclei. We have demonstrated that DACT1 interacts with GSK-3β and β-catenin. DACT1 stabilizes β-catenin via DACT1-induced effects on GSK-3β and directly interacts with β-catenin proteins. The level of phosphorylated GSK-3β at Ser9 is significantly increased following the elevated expression of DACT1. DACT1 mediates the subcellular localization of β-catenin via increasing the level of phosphorylated GSK-3β at Ser9 to inhibit the activity of GSK-3β. Taken together, our study identifies DACT1 as an important positive regulator in colon cancer and suggests a potential strategy for the therapeutic control of the β-catenin-dependent pathway.Wnt/β-连环蛋白（Wnt/β-catenin）信号通路在结肠癌的发生进展中发挥关键作用。DACT1已被证实可通过与散乱蛋白（Dishevelled, Dvl）结合调控Wnt信号通路，而Dvl是经典与非经典Wnt通路的核心介导因子。然而，DACT1在Wnt/β-连环蛋白信号通路中的具体功能仍不明确。本研究证实，DACT1通过调控β-连环蛋白（β-catenin）的稳定性与亚细胞定位，成为结肠癌中重要的正向调控因子。研究表明，DACT1可在体外（in vitro）促进结肠癌细胞增殖、体内（in vivo）促进肿瘤生长，并增强结肠癌细胞的迁移与侵袭潜能。进一步研究发现，DACT1高表达不仅可提升β-连环蛋白的核内与胞质组分水平，还可增加其膜相关组分的含量。DACT1过表达会导致胞质尤其是细胞核内未磷酸化β-连环蛋白的积累显著增多。本研究证实DACT1可与糖原合成激酶3β（GSK-3β）及β-连环蛋白相互结合。DACT1可通过影响GSK-3β的活性稳定β-连环蛋白，并可直接与β-连环蛋白蛋白发生相互作用。当DACT1表达上调后，Ser9位点磷酸化的GSK-3β水平会显著升高。DACT1通过提升Ser9位点磷酸化的GSK-3β水平以抑制GSK-3β活性，从而介导β-连环蛋白的亚细胞定位。综上，本研究明确了DACT1作为结肠癌重要正向调控因子的地位，并为靶向β-连环蛋白依赖型通路的治疗策略提供了潜在方向。