ArticleOncotarget2017
The ISG15-specific protease USP18 regulates stability of PTEN.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L.Military Medical Research · 2026Article
- Understanding protein ISGylation, a multifaceted posttranslational modification.Cell chemical biology · 2026Review
- DIG-DUBs: mechanisms and functions of ISG15 deconjugation by human and viral cross-reactive ubiquitin proteases.Biochemical Society transactions · 2025Article
- Key roles of ubiquitination in regulating critical regulators of cancer stem cell functionality.Genes & diseases · 2025Review
- E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma.Biology direct · 2025Article
- ISGylation: is our genome yearning for such a modification?Acta biochimica et biophysica Sinica · 2025Review
- Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.Nature communications · 2025Article
- HERC5/ISG15 Enhances Glioblastoma Stemness and Tumor Progression by mediating SERBP1protein stability.Neuromolecular medicine · 2025Article
- Bulk and single cells transcriptomes with experimental validation identify USP18 as a novel glioma prognosis and proliferation indicator.Experimental and therapeutic medicine · 2024Article
- Prevotella intermedia boosts OSCC progression through ISG15 upregulation: a new target for intervention.Journal of cancer research and clinical oncology · 2024Article
- Article
- Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.bioRxiv : the preprint server for biology · 2024Article
- The Functional Roles of ISG15/ISGylation in Cancer.Molecules (Basel, Switzerland) · 2023Review
- Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease.Frontiers in cell and developmental biology · 2023Review
- Protein ISGylation: a posttranslational modification with implications for malignant neoplasms.Exploration of targeted anti-tumor therapy · 2023Review
- Analysis of lung cancer-related genetic changes in long-term and low-dose polyhexamethylene guanidine phosphate (PHMG-p) treated human pulmonary alveolar epithelial cells.BMC pharmacology & toxicology · 2022Article
- ISG15 and ISGylation in Human Diseases.Cells · 2022Review
- ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling.Oncogene · 2021Article
- USP18-deficiency in cervical carcinoma is crucial for the malignant behavior of tumor cells in an ERK signal-dependent manner.Oncology letters · 2021Article
- The Ubiquitin-Specific Peptidase USP18 Promotes Lipolysis, Fatty Acid Oxidation, and Lung Cancer Growth.Molecular cancer research : MCR · 2021Article
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.