Yi Qu, Naouel Gharbi, Xing Yuan, Jan Roger Olsen, Pernille Blicher, Bjørn Dalhus, Karl A. Brokstad, Biaoyang Lin, Anne Margrete Øyan, Weidong Zhang, Karl-Henning Kalland, and Xisong Ke
Proceedings of the National Academy of Sciences of the United States of America
2016 vol: 113 issue: 33 pp: 9339-9344 doi: 10.1073/pnas.1604520113
Abstract
Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-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 β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/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/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.
Topics: Axitinib, β-catenin, Asymmetric cell division, SHPRH, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications
