Reference SummaryMustachio LM, Mol Cancer Res 2017 Jul;15(7):905-914

Title

Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer.

Authors

Mustachio LM; Lu Y; Tafe LJ; Memoli V; Rodriguez-Canales J; Mino B; Villalobos PA; Wistuba I; Katayama H; Hanash SM; Roszik J; Kawakami M; Cho KJ; Hancock JF; Chinyengetere F; Hu S; Liu X; Freemantle SJ; Dmitrovsky E

Journal

Mol Cancer Res

Volume

15

Issue

7

Year

2017

Pages

905-914

Abstract

KRAS is 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 of KrasLA2/+ versus cyclin E engineered mouse models. USP18 expression was higher in Kras-driven murine lung cancers, indicating a link between KRAS and USP18 expression in vivo To solidify this association, loss of Usp18 in KrasLA2/+ /Usp18-/- mice was found to significantly reduce lung cancers as compared with parental KrasLA2/+ mice. Finally, translational relevance was confirmed in a human lung cancer panel by showing that USP18 IHC expression was significantly higher in KRAS-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. (c)2017 AACR.

Links

J:243132 – Mouse Genome Informatics
28242811 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB-Krastm3Tyj/+ Lung adenocarcinoma in situ Lung

observed

FVB-Krastm3Tyj/+ Usp18tm1Dez Lung adenocarcinoma in situ Lung

observed

FVB-Krastm3Tyj/+ Lung hyperplasia - atypical - adenomatous Lung

observed

FVB-Krastm3Tyj/+ Usp18tm1Dez Lung hyperplasia - atypical - adenomatous Lung

observed

FVB-Krastm3Tyj/+ Lung tumor Lung

76

FVB-Krastm3Tyj/+ Usp18tm1Dez/+ Lung tumor Lung

84.21

FVB-Krastm3Tyj/+ Usp18tm1Dez Lung tumor Lung

80

FVB-Tg(SFTPC-CCNE1)2Edm Lung tumor - malignant Lung

observed

FVB-Krastm3Tyj/+ Lung tumor - malignant Lung

observed