Oncotarget

Priority Research Papers:

The ISG15-specific protease USP18 regulates stability of PTEN

Lisa Maria Mustachio, Masanori Kawakami, Yun Lu, Jaime Rodriguez-Canales, Barbara Mino, Carmen Behrens, Ignacio Wistuba, Neus Bota-Rabassedas, Jun Yu, J. Jack Lee, Jason Roszik, Lin Zheng, Xi Liu, Sarah J. Freemantle and Ethan Dmitrovsky _

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Abstract

Lisa Maria Mustachio1, Masanori Kawakami2, Yun Lu1, Jaime Rodriguez-Canales3, Barbara Mino3, Carmen Behrens2, Ignacio Wistuba3, Neus Bota-Rabassedas2, Jun Yu4, J. Jack Lee4, Jason Roszik5,6, Lin Zheng2, Xi Liu2, Sarah J. Freemantle1 and Ethan Dmitrovsky1,2,7

1 Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

2 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

5 Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

6 Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

7 Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Ethan Dmitrovsky, email:

Keywords: ISG15, USP18, PTEN, protein stability, and lung cancer

Received: August 23, 2016 Accepted: November 22, 2016 Published: December 12, 2016

Abstract

The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB) ubiquitin specific peptidase 18 (USP18). Using reverse-phase protein arrays (RPPAs), this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue (PTEN) in both murine and human lung cancer cell lines. In contrast, engineered gain of USP18 expression in these same lung cancer cell lines stabilized PTEN protein. Using the protein synthesis inhibitor cycloheximide (CHX), USP18 knockdown was shown to destabilize PTEN whereas USP18 overexpression stabilized PTEN protein. Interestingly, repression of USP18 decreased cytoplasmic PTEN relative to nuclear PTEN protein levels. We sought to identify mechanisms engaged in this PTEN protein destabilization using immunoprecipitation assays and found ISG15 directly conjugated with PTEN. To confirm translational relevance of this work, USP18 and PTEN immunohistochemical expression were compared in comprehensive lung cancer arrays. There was a significant (P < 0.0001) positive correlation and association between PTEN and USP18 protein expression profiles in human lung cancers. Taken together, this study identified PTEN as a previously unrecognized substrate of the ISGylation post-translational modification pathway. The deconjugase USP18 serves as a novel regulator of PTEN stability. This indicates inhibition of ISGylation is therapeutically relevant in cancers.


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