Gliomas are the most common primary brain
malignancies and are associated with a poor prognosis. Here, we showed that the PDZ domain-containing
protein membrane-associated guanylate kinase inverted 3 (MAGI3) was downregulated at the both
mRNA and
protein levels in human
glioma samples. MAGI3 inhibited proliferation, migration, and cell cycle progression of
glioma cells in its overexpression and knockdown studies. By using GST pull-down and co-immunoprecipitation assays, we found that MAGI3 bound to β-
catenin through its PDZ domains and the PDZ-binding motif of β-
catenin. MAGI3 overexpression inhibited β-
catenin transcriptional activity via its interaction with β-
catenin. Consistently, MAGI3 overexpression in
glioma cells C6 suppressed expression of β-
catenin target genes including
Cyclin D1 and Axin2, whereas MAGI3 knockdown in
glioma cells U373 and LN229 enhanced their expression. MAGI3 overexpression decreased growth of C6 subcutaneous
tumors in mice, and inhibited expression of β-
catenin target genes in xenograft
tumors. Furthermore, analysis based on the Gene Expression Omnibus (GEO)
glioma dataset showed association of MAGI3 expression with overall survival and
tumor grade. Finally, we demonstrated negative correlation between MAGI3 expression and activity of Wnt/β-
catenin signaling through GSEA of three public
glioma datasets and immunohistochemical staining of clinical
glioma samples. Taken together, these results identify MAGI3 as a novel
tumor suppressor and provide insight into the pathogenesis of
glioma.