Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer

Lisa Maria Mustachio, Yun Lu, Laura J. Tafe, Vincent Memoli, Jaime Rodriguez-Canales, Barbara Mino, Pamela Andrea Villalobos, Ignacio Wistuba, Hiroyuki Katayama, Samir M. Hanash, Jason Roszik, Masanori Kawakami, Kwang Jin Cho, John F. Hancock, Fadzai Chinyengetere, Shanhu Hu, Xi Liu, Sarah J. Freemantle, Ethan Dmitrovsky

Research output: Contribution to journalArticle

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 halflife 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 Kras LA2/+ 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 Kras LA2/+ /Usp18 -/- mice was found to significantly reduce lung cancers as compared with parental Kras LA2/+ 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 wildtype lung adenocarcinomas.

Original languageEnglish (US)
Pages (from-to)905-914
Number of pages10
JournalMolecular Cancer Research
Volume15
Issue number7
DOIs
StatePublished - Jul 2017
Externally publishedYes

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Lung Neoplasms
Oncogene Proteins
Cyclin E
Protein Synthesis Inhibitors
Deubiquitinating Enzymes
Cycloheximide
Antineoplastic Agents
Half-Life
Cell Membrane
Drug Therapy
Growth
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Mustachio, L. M., Lu, Y., Tafe, L. J., Memoli, V., Rodriguez-Canales, J., Mino, B., ... Dmitrovsky, E. (2017). Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer. Molecular Cancer Research, 15(7), 905-914. https://doi.org/10.1158/1541-7786.MCR-16-0369

Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer. / Mustachio, Lisa Maria; Lu, Yun; Tafe, Laura J.; Memoli, Vincent; Rodriguez-Canales, Jaime; Mino, Barbara; Villalobos, Pamela Andrea; Wistuba, Ignacio; Katayama, Hiroyuki; Hanash, Samir M.; Roszik, Jason; Kawakami, Masanori; Cho, Kwang Jin; Hancock, John F.; Chinyengetere, Fadzai; Hu, Shanhu; Liu, Xi; Freemantle, Sarah J.; Dmitrovsky, Ethan.

In: Molecular Cancer Research, Vol. 15, No. 7, 07.2017, p. 905-914.

Research output: Contribution to journalArticle

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 2017, 'Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer', Molecular Cancer Research, vol. 15, no. 7, pp. 905-914. https://doi.org/10.1158/1541-7786.MCR-16-0369
Mustachio LM, Lu Y, Tafe LJ, Memoli V, Rodriguez-Canales J, Mino B et al. Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer. Molecular Cancer Research. 2017 Jul;15(7):905-914. https://doi.org/10.1158/1541-7786.MCR-16-0369
Mustachio, Lisa Maria ; Lu, Yun ; Tafe, Laura J. ; Memoli, Vincent ; Rodriguez-Canales, Jaime ; Mino, Barbara ; Villalobos, Pamela Andrea ; Wistuba, Ignacio ; Katayama, Hiroyuki ; Hanash, Samir M. ; Roszik, Jason ; Kawakami, Masanori ; Cho, Kwang Jin ; Hancock, John F. ; Chinyengetere, Fadzai ; Hu, Shanhu ; Liu, Xi ; Freemantle, Sarah J. ; Dmitrovsky, Ethan. / Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 7. pp. 905-914.
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AU - Rodriguez-Canales, Jaime

AU - Mino, Barbara

AU - Villalobos, Pamela Andrea

AU - Wistuba, Ignacio

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AU - Hanash, Samir M.

AU - Roszik, Jason

AU - Kawakami, Masanori

AU - Cho, Kwang Jin

AU - Hancock, John F.

AU - Chinyengetere, Fadzai

AU - Hu, Shanhu

AU - Liu, Xi

AU - Freemantle, Sarah J.

AU - Dmitrovsky, Ethan

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