β-catenin/Tcf-4 complex transcriptionally regulates AKT1 in glioma.

Increasing evidence suggests that interplays between Wnt/β-catenin and PI3K/AKT signaling cascades are involved in tumor development and progression. However, the exact mechanism in glioma is not well known. Using aspirin, we found that the expression levels of AKT1 in glioma cells significantly correlated with the transcriptional activity of β-catenin. Similar observations were made when we subjected glioma cells to treatment with Tcf4 siRNA. Moreover, both aspirin and Tcf4 siRNA can suppress the proliferation and induce apoptosis of glioma. In addition, our analysis of the gene promoter of AKT1 revealed multiple putative Tcf-4 binding sites. In support of the concept that β-catenin/Tcf-4 is a transcriptional regulator for AKT1, results from our chromatin immunoprecipitation studies and luciferase assay showed that β-catenin/Tcf-4 binds to the potential binding sites in the gene promoter of AKT1. Furthermore, using immunohistochemistry, we found that Tcf-4 protein expression increased significantly in high-grade glioma in comparison to low-grade glioma and correlated with AKT1 expression. In conclusion, our results support the concept that β-catenin/Tcf-4 directly regulates AKT1 in glioma, and these two proteins may cooperate with each other in exerting their oncogenic effects in glioma.