title: USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.
abstract: 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.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857;
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.affiliation: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Walker
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
authors.forename: Robert
authors.initials: R
authors.lastname: Young
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
authors.forename: Laura
authors.initials: L
authors.lastname: Quick
authors.affiliation: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295;
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Orgel
authors.affiliation: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295;
authors.forename: Meagan
authors.initials: M
authors.lastname: Ryan
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857;
authors.forename: Priti
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
authors.forename: Ian C
authors.initials: IC
authors.lastname: Henrich
authors.affiliation: Department of Automated Biotechnology, Merck Research Laboratories, North Wales, PA 19454; National Center for Advancing Translation Sciences/NIH, Rockville, MD 20850;
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Department of Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA 19454;
authors.forename: Shane
authors.initials: S
authors.lastname: Marine
authors.affiliation: Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806;
authors.forename: Brian S
authors.initials: BS
authors.lastname: Roberts
authors.affiliation: Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109; Seattle Genetics, Bothell, WA 98021;
authors.forename: William T
authors.initials: WT
authors.lastname: Arthur
authors.affiliation: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195; Institute for Stem Cell and Regenerative Medicine at the University of Washington, Seattle, WA 98195;
authors.forename: Jason D
authors.initials: JD
authors.lastname: Berndt
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.affiliation: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195; Institute for Stem Cell and Regenerative Medicine at the University of Washington, Seattle, WA 98195; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
authors.forename: David M
authors.identifier: 0000-0001-6976-850X
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Chou
authors.affiliation: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D060449:Wnt Signaling Pathway
chemical_list: C501126:DKK1 protein, human; D004268:DNA-Binding Proteins; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; C572950:ZNRF3 protein, human; C473330:USP6 protein, human; D043222:Ubiquitin Thiolesterase
keywords: Frizzled; USP6; Wnt signaling; ubiquitin; ubiquitin-specific protease