title: Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma.
abstract: ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications.
authors.affiliation: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Harish
authors.initials: H
authors.lastname: Potu
authors.affiliation: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Luke F
authors.initials: LF
authors.lastname: Peterson
authors.affiliation: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Malathi
authors.initials: M
authors.lastname: Kandarpa
authors.affiliation: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Pal
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
authors.forename: Hanshi
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Durham
authors.affiliation: Departments of Pathology and Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical Sciences Program, Indiana University Bloomington, 1001 Third St, Bloomington, Indiana 47405, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hollenhorst
authors.affiliation: Children's Research Institute and Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ugur
authors.identifier: 0000-0003-3785-5275
authors.initials: U
authors.lastname: Eskiocak
authors.affiliation: Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C494041:ETS1 protein, human; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; C506234:USP9X protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D043222:Ubiquitin Thiolesterase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human