title: Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer.
abstract: KRASis frequently mutated in lung cancers and is associated with aggressive biology and chemotherapy resistance. Therefore, innovative approaches are needed to treat these lung cancers. Prior work implicated the IFN-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having antineoplastic activity by regulating lung cancer growth and oncoprotein stability. This study demonstrates that USP18 affects the stability of the KRAS oncoprotein. Interestingly, loss of USP18 reduced KRAS expression, and engineered gain of USP18 expression increased KRAS protein levels in lung cancer cells. Using the protein synthesis inhibitor cycloheximide, USP18 knockdown significantly reduced the half-life of KRAS, but gain of USP18 expression significantly increased its stability. Intriguingly, loss of USP18 altered KRAS subcellular localization by mislocalizing KRAS from the plasma membrane. To explore the biologic consequences, immunohistochemical (IHC) expression profiles of USP18 were compared in lung cancers ofKrasLA2/+versus cyclin E engineered mouse models. USP18 expression was higher inKras-driven murine lung cancers, indicating a link between KRAS and USP18 expressionin vivoTo solidify this association, loss ofUsp18inKrasLA2/+/Usp18-/-mice was found to significantly reduce lung cancers as compared with parentalKrasLA2/+mice. Finally, translational relevance was confirmed in a human lung cancer panel by showing that USP18 IHC expression was significantly higher inKRAS-mutant versus wild-type lung adenocarcinomas.Implications:Taken together, this study highlights a new way to combat the oncogenic consequences of activated KRAS in lung cancer by inhibiting the DUB USP18.Mol Cancer Res; 15(7); 905-14. ©2017 AACR.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Lisa Maria
authors.initials: LM
authors.lastname: Mustachio
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Tafe
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.|Norris Cotton Cancer Center, Geisel School of Medicine, Hanover, New Hampshire and Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Vincent
authors.initials: V
authors.lastname: Memoli
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mino
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pamela Andrea
authors.initials: PA
authors.lastname: Villalobos
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katayama
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawakami
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas McGovern Medical School, Houston, Texas.
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas McGovern Medical School, Houston, Texas.
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Fadzai
authors.initials: F
authors.lastname: Chinyengetere
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Shanhu
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Freemantle
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. edmitrovsky@mdanderson.org.|Norris Cotton Cancer Center, Geisel School of Medicine, Hanover, New Hampshire and Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.|Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D003513:Cycloheximide / Q000008:administration & dosage; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009154:Mutation; D014176:Protein Biosynthesis / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D043222:Ubiquitin Thiolesterase
chemical_list: D019927:Cyclin E; C117307:KRAS protein, human; D003513:Cycloheximide; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; D016283:Proto-Oncogene Proteins p21(ras)