IRX3-CDK14 axis promotes glioblastoma progression by regulating LRP6-mediated canonical Wnt/β-catenin pathway

Iroquois Homeobox 3 (IRX3), a highly conserved member of the Iroquois homeobox gene family, has been implicated in obesity through its regulation of fat mass and obesity-associated (FTO) gene. Emerging evidence indicates that IRX3 plays critical roles in the development of some cancers, but the specific functions and molecular mechanisms of IRX3 in glioblastoma (GBM) remain unknown. Here, we demonstrate that IRX3 is highly expressed in GBM and significantly correlated with poor prognosis of patients. IRX3 promotes cell proliferation, colony formation, migration, and invasion in vitro and brain tumor growth in vivo. Mechanistically, IRX3 promotes the transcription of CDK14 (Cyclin Dependent Kinase 14) by binding to its promoter, which in turn stabilizes β-catenin expression through restraining its ubiquitination degradation, thereby activating the canonical Wnt/β-catenin pathway and promoting GBM growth. In addition, we identify LRP6 (LDL receptor-related protein 6) as a crucial regulatory factor in maintaining IRX3-mediated stabilization of β-catenin. Our results demonstrate that IRX3 serves as a promising biomarker for patients with GBM, and targeting the IRX3-CDK14-LRP6 axis may represent a viable treatment approach for GBM.