Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 33, Pages 9339-9344Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1604520113
Keywords
axitinib; beta-catenin; asymmetric cell division; SHPRH
Categories
Funding
- Tordis and Fritz C. Rieber's Foundation
- Bergen Medical Research Foundation
- Helse Vest Grants [911778, 911626, 911747, 912062]
- Centre for Cancer Biomarkers
- Research Council of Norway Grant [223250/F50]
- South-Eastern Norway Regional Health Authority Grant (Regional Core Facility for Structural Biology) [2015095]
- Norwegian Cancer Society Grant [803148]
- Natural Science Foundation of China Grant [81230090]
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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.
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