Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Oncogenic mutations of the Wnt (wingless)/beta-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/beta-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/beta-catenin signaling in cancer cells, zebrafish, and Apc(min/+) mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear beta-catenin degradation independent of the GSK3 beta (glycogen synthase kinase3 beta)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/beta-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of beta-catenin. Our findings suggest a previously unreported mechanism of nuclear beta-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear beta-catenin activation.