title: Jak1-STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis.
abstract: Bone and soft tissue tumors (BSTT) are relatively poorly understood, hampering the development of effective therapies. Here we report a role for the ubiquitin-specific protease 6 (USP6)/TRE17 oncogene, which is overexpressed upon chromosome translocation in various human tumors, including aneurysmal bone cyst (ABC), and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors, which recapitulate key features of ABC and nodular fasciitis; however, the identity of USP6's relevant substrates has been obscure. Here we report that the Jak1-STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of nodular fasciitis confirmed the activation of a Jak1-STAT3 gene signature in vivo Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression. Cancer Res; 76(18); 5337-47. ©2016 AACR.
authors.affiliation: Division of Cell Pathology, Department Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Laura
authors.initials: L
authors.lastname: Quick
authors.affiliation: Division of Cell Pathology, Department Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Young
authors.affiliation: Division of Cell Pathology, Department Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Henrich
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.affiliation: Division of Cell Pathology, Department Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania. mmc@mail.med.upenn.edu.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Chou
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053613:Janus Kinase 1 / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C473330:USP6 protein, human; D043222:Ubiquitin Thiolesterase