
USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.
The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.
Duke Scholars
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Related Subject Headings
- Wnt Signaling Pathway
- Ubiquitination
- Ubiquitin-Protein Ligases
- Ubiquitin Thiolesterase
- Proto-Oncogene Proteins
- Oncogene Proteins
- Neoplasms, Experimental
- Mice
- Low Density Lipoprotein Receptor-Related Protein-6
- Intercellular Signaling Peptides and Proteins
Citation

Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Wnt Signaling Pathway
- Ubiquitination
- Ubiquitin-Protein Ligases
- Ubiquitin Thiolesterase
- Proto-Oncogene Proteins
- Oncogene Proteins
- Neoplasms, Experimental
- Mice
- Low Density Lipoprotein Receptor-Related Protein-6
- Intercellular Signaling Peptides and Proteins