Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth

beta-catenin is a crucial signal transduction molecule in the Wnt/beta-catenin signal pathway, and increased beta-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for beta-catenin overexpression have remained elusive. Here we show that the deubiquitinase USP9X stabilizes beta-catenin and thereby promotes high grade glioma cell growth. USP9X binds beta-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark beta-catenin for proteasomal degradation. Increased USP9X expression correlates with increased beta-catenin protein in high grade glioma tissues. Moreover, patients with high grade glioma overexpressing USP9X have a poor prognosis. Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells. Interestingly, c-Myc and cyclinD1, which are important downstream target genes in the Wnt/beta-catenin signal pathway, also show decreased expression in cells with siRNA-mediated down-regulation of USP9X. Down-regulation of USP9X also consistently inhibits the tumorigenicity of primary glioma cells in vivo. In summary, these results indicate that USP9X stabilizes beta-catenin and activates Wnt/beta-catenin signal pathway to promote glioma cell proliferation and survival. USP9X could also potentially be a novel therapeutic target for high grade gliomas.