USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Madan, B; Walker, MP; Young, R; Quick, L; Orgel, KA; Ryan, M; Gupta, P; Henrich, IC; Ferrer, M; Marine, S; Roberts, BS; Arthur, WT; Berndt, JD; Oliveira, AM; Moon, RT; Virshup, DM; Chou, MM; Major, MB

Published Date

  • May 24, 2016

Published In

Volume / Issue

  • 113 / 21

Start / End Page

  • E2945 - E2954

PubMed ID

  • 27162353

Pubmed Central ID

  • 27162353

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1605691113


  • eng

Conference Location

  • United States