PMID- 27162353 OWN - NLM STAT- MEDLINE DCOM- 20161222 LR - 20220408 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 21 DP - 2016 May 24 TI - USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. PG - E2945-54 LID - 10.1073/pnas.1605691113 [doi] AB - 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/beta-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. FAU - Madan, Babita AU - Madan B AD - Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857; FAU - Walker, Matthew P AU - Walker MP AD - Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295; FAU - Young, Robert AU - Young R AD - Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; FAU - Quick, Laura AU - Quick L AD - Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; FAU - Orgel, Kelly A AU - Orgel KA AD - Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295; FAU - Ryan, Meagan AU - Ryan M AD - Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295; FAU - Gupta, Priti AU - Gupta P AD - Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857; FAU - Henrich, Ian C AU - Henrich IC AD - Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; FAU - Ferrer, Marc AU - Ferrer M AD - Department of Automated Biotechnology, Merck Research Laboratories, North Wales, PA 19454; National Center for Advancing Translation Sciences/NIH, Rockville, MD 20850; FAU - Marine, Shane AU - Marine S AD - Department of Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA 19454; FAU - Roberts, Brian S AU - Roberts BS AD - Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806; FAU - Arthur, William T AU - Arthur WT AD - Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109; Seattle Genetics, Bothell, WA 98021; FAU - Berndt, Jason D AU - Berndt JD AD - 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; FAU - Oliveira, Andre M AU - Oliveira AM AD - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905. FAU - Moon, Randall T AU - Moon RT AD - 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. FAU - Virshup, David M AU - Virshup DM AUID- ORCID: 0000-0001-6976-850X AD - 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. FAU - Chou, Margaret M AU - Chou MM AD - 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. FAU - Major, Michael B AU - Major MB AD - 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. LA - eng GR - R21 CA178760/CA/NCI NIH HHS/United States GR - T32 CA009156/CA/NCI NIH HHS/United States GR - T32 GM008076/GM/NIGMS NIH HHS/United States GR - P30 CA016086/CA/NCI NIH HHS/United States GR - R21 CA178601/CA/NCI NIH HHS/United States GR - R01 CA168452/CA/NCI NIH HHS/United States GR - DP2 OD007149/OD/NIH HHS/United States GR - T32 CA071341/CA/NCI NIH HHS/United States GR - R01 CA187799/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160509 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (DKK1 protein, human) RN - 0 (DNA-Binding Proteins) RN - 0 (Frizzled Receptors) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (LRP6 protein, human) RN - 0 (Low Density Lipoprotein Receptor-Related Protein-6) RN - 0 (Oncogene Proteins) RN - 0 (Proto-Oncogene Proteins) RN - EC 2.3.2.27 (RNF43 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (ZNRF3 protein, human) RN - EC 3.4.19.12 (USP6 protein, human) RN - EC 3.4.19.12 (Ubiquitin Thiolesterase) SB - IM MH - Animals MH - DNA-Binding Proteins/genetics/*metabolism MH - Frizzled Receptors/genetics/*metabolism MH - HEK293 Cells MH - HeLa Cells MH - Humans MH - Intercellular Signaling Peptides and Proteins/genetics/metabolism MH - Low Density Lipoprotein Receptor-Related Protein-6/genetics/metabolism MH - Mice MH - Neoplasms, Experimental/genetics/*metabolism MH - Oncogene Proteins/genetics/*metabolism MH - Proto-Oncogene Proteins/genetics/*metabolism MH - Ubiquitin Thiolesterase/genetics/*metabolism MH - Ubiquitin-Protein Ligases/genetics/metabolism MH - *Ubiquitination MH - *Wnt Signaling Pathway PMC - PMC4889410 OTO - NOTNLM OT - Frizzled OT - USP6 OT - Wnt signaling OT - ubiquitin OT - ubiquitin-specific protease COIS- The authors declare no conflict of interest. EDAT- 2016/05/11 06:00 MHDA- 2016/12/23 06:00 PMCR- 2016/11/24 CRDT- 2016/05/11 06:00 PHST- 2016/05/11 06:00 [entrez] PHST- 2016/05/11 06:00 [pubmed] PHST- 2016/12/23 06:00 [medline] PHST- 2016/11/24 00:00 [pmc-release] AID - 1605691113 [pii] AID - 201605691 [pii] AID - 10.1073/pnas.1605691113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2945-54. doi: 10.1073/pnas.1605691113. Epub 2016 May 9.