Gene Summary

Gene:ISG15; ISG15 ubiquitin like modifier
Aliases: G1P2, IP17, UCRP, IFI15, IMD38, hUCRP
Summary:The protein encoded by this gene is a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been ascribed to the encoded protein, including chemotactic activity towards neutrophils, direction of ligated target proteins to intermediate filaments, cell-to-cell signaling, and antiviral activity during viral infections. While conjugates of this protein have been found to be noncovalently attached to intermediate filaments, this protein is sometimes secreted. [provided by RefSeq, Dec 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ubiquitin-like protein ISG15
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (13)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ISG15 (cancer-related)

Yu Y, Blokhuis BR, Garssen J, Redegeld FA
A Transcriptomic Insight into the Impact of Colon Cancer Cells on Mast Cells.
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34⁺ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal-e.g., TLR2 ligands-may modify their responses in the cancer milieu.

Sun Y, Xiaoyan H, Yun L, et al.
Identification of Key Candidate Genes and Pathways for Relationship between Ovarian Cancer and Diabetes Mellitus Using Bioinformatical Analysis
Asian Pac J Cancer Prev. 2019; 20(1):145-155 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is one of the three major gynecologic cancers in the world. The aim of this study is to find the relationship between ovarian cancer and diabetes mellitus by using the genetic screening technique. By GEO database query and related online tools of analysis, we analyzed 185 cases of ovarian cancer and 10 control samples from GSE26712, and a total of 379 different genes were identified, including 104 up-regulated genes and 275 down-regulated genes. The up-regulated genes were mainly enriched in biological processes, including cell adhesion, transcription of nucleic acid and biosynthesis, and negative regulation of cell metabolism. The down-regulated genes were enriched in cell proliferation, migration, angiogenesis and macromolecular metabolism. Protein-protein interaction was analyzed by network diagram and module synthesis analysis. The top ten hub genes (CDC20, H2AFX, ENO1, ACTB, ISG15, KAT2B, HNRNPD, YWHAE, GJA1 and CAV1) were identified, which play important roles in critical signaling pathways that regulate the process of oxidation-reduction reaction and carboxylic acid metabolism. CTD analysis showed that the hub genes were involved in 1,128 distinct diseases (bonferroni-corrected P<0.05). Further analysis by drawing the Kaplan-Meier survival curve indicated that CDC20 and ISG15 were statistically significant (P<0.05). In conclusion, glycometabolism was related to ovarian cancer and genes and proteins in glycometabolism could serve as potential targets in ovarian cancer treatment.

Dzimianski JV, Beldon BS, Daczkowski CM, et al.
Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity.
PLoS Pathog. 2019; 15(1):e1007515 [PubMed] Free Access to Full Article Related Publications
Post-translational modification of host and viral proteins by ubiquitin (Ub) and Ub-like proteins, such as interferon stimulated gene product 15 (ISG15), plays a key role in response to infection. Viruses have been increasingly identified that contain proteases possessing deubiquitinase (DUB) and/or deISGylase functions. This includes viruses in the Nairoviridae family that encode a viral homologue of the ovarian tumor protease (vOTU). vOTU activity was recently demonstrated to be critical for replication of the often-fatal Crimean-Congo hemorrhagic fever virus, with DUB activity suppressing the type I interferon responses and deISGylase activity broadly removing ISG15 conjugated proteins. There are currently about 40 known nairoviruses classified into fourteen species. Recent genomic characterization has revealed a high degree of diversity, with vOTUs showing less than 25% amino acids identities within the family. Previous investigations have been limited to only a few closely related nairoviruses, leaving it unclear what impact this diversity has on vOTU function. To probe the effects of vOTU diversity on enzyme activity and specificity, we assessed representative vOTUs spanning the Nairoviridae family towards Ub and ISG15 fluorogenic substrates. This revealed great variation in enzymatic activity and specific substrate preferences. A subset of the vOTUs were further assayed against eight biologically relevant di-Ub substrates, uncovering both common trends and distinct preferences of poly-Ub linkages by vOTUs. Four novel X-ray crystal structures were obtained that provide a biochemical rationale for vOTU substrate preferences and elucidate structural features that distinguish the vOTUs, including a motif in the Hughes orthonairovirus species that has not been previously observed in OTU domains. Additionally, structure-informed mutagenesis provided the first direct evidence of a second site involved in di-Ub binding for vOTUs. These results provide new insight into nairovirus evolution and pathogenesis, and further enhances the development of tools for therapeutic purposes.

Cruz-Ramos E, Macías-Silva M, Sandoval-Hernández A, Tecalco-Cruz AC
Non-muscle myosin IIA is post-translationally modified by interferon-stimulated gene 15 in breast cancer cells.
Int J Biochem Cell Biol. 2019; 107:14-26 [PubMed] Related Publications
ISG15 (interferon-stimulated gene 15) exists as free ISG15 or conjugated ISG15 modifying its target proteins via ISGylation. Few proteins have been identified and studied as ISGylation targets, and their relevance is not completely clear. Here, we isolated ISG15 from MDA-MB-231 breast cancer cells using immunoprecipitation and identified non-muscle myosin IIA (NMIIA) using mass spectrometry as endogenously associated with ISG15. The identification of NMIIA as an ISG15-interacting protein was important, because levels of NMIIA mRNA were not deregulated in all breast cancers, and because our in silico analysis indicated that NMIIA was the target of different posttranslational modifications and had an interactome associated with cytoskeletal remodeling. Furthermore, our experimental assays of co-immunoprecipitation and immunofluorescence confirmed that ISG15 was covalently associated with NMIIA in the cytoplasm of breast cancer cells and that interferon γ (IFN-γ) increased this association without alterations in the NMIIA levels. Thus, NMIIA ISGylation is regulated by IFN-γ, and this modification may modulate its interactions with proteins that remodel the cytoskeleton, participating in the growth and progression of mammary tumors.

Islam T, Rahman R, Gov E, et al.
Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.
OMICS. 2018; 22(6):422-436 [PubMed] Related Publications
The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Liu Z, Ma M, Yan L, et al.
miR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells.
Cancer Biomark. 2018; 22(3):453-466 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Interferon-α (IFN-α) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-α.
METHODS: We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN-α sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples.
RESULTS: The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-α, whereas the shRNA-mediated knock down of ISG15 expression increased apoptosis in both Huh7 and LH86 cells. We identified a putative miR-370 target site in the 3'-UTR in the ISG15 mRNA, and the level of miR-370 expression in HCC cell lines reflected the level of IFN-α-induced apoptosis exhibited by each. Both HCC cell lines and tumor samples had significantly lower levels of miR-370 than the control cells and tissues (P< 0.05). The overexpression of miR-370 in IFN-α-treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN-α compared with the control tumors.
CONCLUSIONS: Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN-α sensitivity and that miR-370 might be a useful prognostic marker for HCC patients.

Tecalco-Cruz AC, Cruz-Ramos E
Protein ISGylation and free ISG15 levels are increased by interferon gamma in breast cancer cells.
Biochem Biophys Res Commun. 2018; 499(4):973-978 [PubMed] Related Publications
The induction of ISG15 by interferon (IFN)-α/β and subsequent protein ISGylation has been demonstrated in several cell types. However, regulation of free ISG15 levels and ISGylation by other IFNs and its implications in some carcinomas have not yet been completely evaluated. Here, we demonstrated that free ISG15 and ISGylation levels are enhanced by IFN-γ treatment in the estrogen receptor-α-positive and -negative breast cancer cells, MCF-7 and MDA-MB-231, respectively. Specifically, IFN-γ increases free ISG15 levels in the cytoplasm and ISGylation in the nucleus and cytoplasm, but in a manner distinct between MCF-7 and MDA-MB-231 cells. Therefore, free ISG15 and ISGylation may play central roles in mammary tumors by differentially modulating certain tumorigenic characteristics of estrogen receptor-α-positive and -negative breast cancer cells.

Yuan H, Zhou W, Yang Y, et al.
ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/β-catenin signaling pathway.
Exp Cell Res. 2018; 367(1):47-55 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in China with a poor prognosis. Most ESCC patients were diagnosed at advanced stages, losing the opportunity for surgical excision. Hence, it remains a pressing work to identify biomarkers for early detection, prognosis prediction and targeting therapies in ESCC. Interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, and is involved in the post-translational modification (PTMs) of multiple proteins. However, the molecular functions of ISG15 in ESCC remain unclear. In this work, we found that ISG15 was aberrantly expressed in ESCC tissues and cell lines. Enhanced protein level of ISG15 promoted cellular malignant phenotypes including proliferation, migration, invasion and tumor formation in vivo. Consistently, reduction of ISG15 attenuated the cellular malignant phenotype in ESCC cell lines. Furthermore, gene-expression profiles suggested that the differentially expressed ISG15 affected the expression of a panel of genes enriched in the cell adherens junction, such as c-MET. Notably, as a secreted protein, the concentration of ISG15 was elevated in ESCC plasma than healthy individuals, acting as a potential diagnostic marker. Taken together, our results suggested a tumor promotion role of ISG15 in ESCC via c-MET/Fyn/β-catenin pathway.

Mustachio LM, Lu Y, Kawakami M, et al.
Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target.
Cancer Res. 2018; 78(3):587-592 [PubMed] Free Access to Full Article Related Publications
Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target. USP18 is the major DUB that removes IFN-stimulated gene 15 (ISG15) from conjugated proteins. Prior work discovered that engineered loss of USP18 increases ISGylation and in contrast to its gain decreases cancer growth by destabilizing growth-regulatory proteins. Loss of USP18 reduced cancer cell growth by triggering apoptosis. Genetic loss of USP18 repressed cancer formation in engineered murine lung cancer models. The translational relevance of USP18 was confirmed by finding its expression was deregulated in malignant versus normal tissues. Notably, the recent elucidation of the USP18 crystal structure offers a framework for developing an inhibitor to this DUB. This review summarizes strong evidence for USP18 as a previously unrecognized pharmacologic target in oncology.

Wang R, Li J, Zhao Y, et al.
Investigating the therapeutic potential and mechanism of curcumin in breast cancer based on RNA sequencing and bioinformatics analysis.
Breast Cancer. 2018; 25(2):206-212 [PubMed] Related Publications
BACKGROUND: Breast cancer is a prevalent cancer in female. This study aims to investigate the therapeutic potential and mechanism of curcumin in breast cancer.
METHODS: After cultivation, human breast cancer cells (MCF-7 cells) were treated with 0.1% (v/v) 15 µmol/ml curcumin-dimethylsulfoxide solution and 0.1% (v/v) dimethylsulfoxide, respectively, at 37 °C and 5% CO
RESULTS: After DEGs screening, 347 DEGs were identified. Up-regulated DEGs were enriched in 14 functions and 3 pathways, and associated with 12 drugs. Down-regulated DEGs were enriched in 14 functions and 9 pathways, and associated with 14 drugs. Moreover, 5 DEGs were associated with breast cancer, including PGAP3, MAP3K1, SERPINE1, PON2, and GSTO2. PPI network was constructed, and the top DEGs were FOS, VIM, FGF2, MAPK1, SPARC, TOMM7, PSMB10, TCEB2, SOCS1, COL4A1, UQCR11, SERPINE1, and ISG15.
CONCLUSION: Curcumin might have therapeutic potential in breast cancer through regulating breast cancer-related genes, including SERPINE1, PGAP3, MAP3K1, MAPK1, GSTO2, VIM, SPARC, and FGF2. However, validations are required.

Titus AJ, Way GP, Johnson KC, Christensen BC
Deconvolution of DNA methylation identifies differentially methylated gene regions on 1p36 across breast cancer subtypes.
Sci Rep. 2017; 7(1):11594 [PubMed] Free Access to Full Article Related Publications
Breast cancer is a complex disease consisting of four distinct molecular subtypes. DNA methylation-based (DNAm) studies in tumors are complicated further by disease heterogeneity. In the present study, we compared DNAm in breast tumors with normal-adjacent breast samples from The Cancer Genome Atlas (TCGA). We constructed models stratified by tumor stage and PAM50 molecular subtype and performed cell-type reference-free deconvolution to control for cellular heterogeneity. We identified nineteen differentially methylated gene regions (DMGRs) in early stage tumors across eleven genes (AGRN, C1orf170, FAM41C, FLJ39609, HES4, ISG15, KLHL17, NOC2L, PLEKHN1, SAMD11, WASH5P). These regions were consistently differentially methylated in every subtype and all implicated genes are localized to the chromosomal cytoband 1p36.3. Seventeen of these DMGRs were independently validated in a similar analysis of an external data set. The identification and validation of shared DNAm alterations across tumor subtypes in early stage tumors advances our understanding of common biology underlying breast carcinogenesis and may contribute to biomarker development. We also discuss evidence of the specific importance and potential function of 1p36 in cancer.

Scholte FEM, Zivcec M, Dzimianski JV, et al.
Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease.
Cell Rep. 2017; 20(10):2396-2407 [PubMed] Free Access to Full Article Related Publications
Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines.

Villarroya-Beltri C, Guerra S, Sánchez-Madrid F
ISGylation - a key to lock the cell gates for preventing the spread of threats.
J Cell Sci. 2017; 130(18):2961-2969 [PubMed] Related Publications
Interferon stimulated gene 15 (ISG15) is an ubiquitin-like protein whose expression and conjugation to targets (ISGylation) is induced by infection, interferon (IFN)-α and -β, ischemia, DNA damage and aging. Attention has historically focused on the antiviral effects of ISGylation, which blocks the entry, replication or release of different intracellular pathogens. However, recently, new functions of ISGylation have emerged that implicate it in multiple cellular processes, such as DNA repair, autophagy, protein translation and exosome secretion. In this Review, we discuss the induction and conjugation of ISG15, as well as the functions of ISGylation in the prevention of infections and in cancer progression. We also offer a novel perspective with regard to the latest findings on this pathway, with special attention to the role of ISGylation in the inhibition of exosome secretion, which is mediated by fusion of multivesicular bodies with lysosomes. Finally, we propose that under conditions of stress or infection, ISGylation acts as a defense mechanism to inhibit normal protein translation by modifying protein kinase R (PKR, also known as EIF2AK2), while any newly synthesized proteins are being tagged and thus marked as potentially dangerous. Then, the endosomal system is re-directed towards protein degradation at the lysosome, to effectively 'lock' the cell gates and thus prevent the spread of pathogens, prions and deleterious aggregates through exosomes.

Wang Z, Zhu WG, Xu X
Ubiquitin-like modifications in the DNA damage response.
Mutat Res. 2017; 803-805:56-75 [PubMed] Related Publications
Genomic DNA is damaged at an extremely high frequency by both endogenous and environmental factors. An improper response to DNA damage can lead to genome instability, accelerate the aging process and ultimately cause various human diseases, including cancers and neurodegenerative disorders. The mechanisms that underlie the cellular DNA damage response (DDR) are complex and are regulated at many levels, including at the level of post-translational modification (PTM). Since the discovery of ubiquitin in 1975 and ubiquitylation as a form of PTM in the early 1980s, a number of ubiquitin-like modifiers (UBLs) have been identified, including small ubiquitin-like modifiers (SUMOs), neural precursor cell expressed, developmentally down-regulated 8 (NEDD8), interferon-stimulated gene 15 (ISG15), human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10), ubiquitin-fold modifier 1 (UFRM1), URM1 ubiquitin-related modifier-1 (URM1), autophagy-related protein 12 (ATG12), autophagy-related protein 8 (ATG8), fan ubiquitin-like protein 1 (FUB1) and histone mono-ubiquitylation 1 (HUB1). All of these modifiers have known roles in the cellular response to various forms of stress, and delineating their underlying molecular mechanisms and functions is fundamental in enhancing our understanding of human disease and longevity. To date, however, the molecular mechanisms and functions of these UBLs in the DDR remain largely unknown. This review summarizes the current status of PTMs by UBLs in the DDR and their implication in cancer diagnosis, therapy and drug discovery.

Du Z, Cai C, Sims M, et al.
The effects of type I interferon on glioblastoma cancer stem cells.
Biochem Biophys Res Commun. 2017; 491(2):343-348 [PubMed] Related Publications
Glioblastomas (GBMs) are highly invasive brain tumors that are extremely deadly. The highly aggressive nature of GBM as well as its heterogeneity at the molecular and cellular levels has been attributed to a rare subpopulation of GBM stem-like cells (GSCs). Interferons (IFNs) are a family of endogenous antiviral proteins that have anticancer activity in vitro, and have been used clinically to treat GBM. IFN inhibits the proliferation of various established GBM cell lines, but the effects of IFNs on GSCs remain relatively unknown. The present study explored the effects of IFN on the proliferation and the differentiation capacity of GSCs isolated from GBM patient-derived xenolines (PDXs) grown as xenografts in immunocompromised mice. We show that IFN inhibits the proliferation of GSCs, inhibits the sphere forming capacity of GSCs that is a hallmark of cancer stem cells, and inhibits the ability of GSCs to differentiate into astrocytic cells. In addition, we show that IFN induces transient STAT3 activation in GSCs, while induction of astrocytic differentiation in GSCs results in sustained STAT3 activation.

Ayub SG, Kaul D
miR-2909 regulates ISGylation system via STAT1 signalling through negative regulation of SOCS3 in prostate cancer.
Andrology. 2017; 5(4):790-797 [PubMed] Related Publications
One of the well-document strategies adopted by tumour cells for progression is to evade immune surveillance mechanisms. An understanding of the tight interaction between immunity and progression of cancer can provide novel treatment options for different malignancies including prostate cancer (PCa). Here, we have shown that AATF genome encoded miR-2909, known to play role both in immunity and cancer upregulates various interferon stimulating genes (ISGs) including ISGylation system through STAT1. Our results revealed that miR-2909 up-regulates STAT1 through negative regulation of SOCS3 and not through up-regulation of Type 1 interferon (IFN) production. It was observed that inhibition of ISGylation reduced the proliferation potential of PCa cells. Furthermore, androgens were found to negatively regulate ISGylation in LNCaP cells through androgen receptor signalling independently of miR-2909. TGF-β mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression. Collectively, these studies suggest that miR-2909 could play a vital role in prostate carcinogenesis through modulation of ISGylation system and TGFβ signalling via STAT1.

Mustachio LM, Lu Y, Tafe LJ, et al.
Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer.
Mol Cancer Res. 2017; 15(7):905-914 [PubMed] Free Access to Full Article Related Publications

Falvey CM, O'Donovan TR, El-Mashed S, et al.
UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells.
Oncotarget. 2017; 8(14):23479-23491 [PubMed] Free Access to Full Article Related Publications
Esophageal cancer remains a poor prognosis cancer due to advanced stage of presentation and drug resistant disease. To understand the molecular mechanisms influencing response to chemotherapy, we examined genes that are differentially expressed between drug sensitive, apoptosis competent esophageal cancer cells (OE21, OE33, FLO-1) and those which are more resistant and do not exhibit apoptosis (KYSE450 and OE19). Members of the ISG15 (ubiquitin-like) protein modification pathway, including UBE2L6 and ISG15, were found to be more highly expressed in the drug sensitive cell lines. In this study, we evaluated the contribution of these proteins to the response of drug sensitive cells. Depletion of UBE2L6 or ISG15 with siRNA did not influence caspase-3 activation or nuclear fragmentation following treatment with 5-fluorouracil (5-FU). We assessed autophagy by analysis of LC3II expression and Cyto-ID staining. Depletion of either ISG15 or UBE2L6 resulted in enhanced endogenous autophagic flux. An increase in autophagic flux was also observed following treatment with cytotoxic drugs (5-FU, rapamycin). In ISG15 depleted cells, this increase in autophagy was associated with improved recovery of drug treated cells. In contrast, UBE2L6 depleted cells, did not show enhanced recovery. UBE2L6 may therefore influence additional targets that limit the pro-survival effect of ISG15 depletion. These data identify UBE2L6 and ISG15 as novel inhibitors of autophagy, with the potential to influence chemosensitivity in esophageal cancer cells.

Zhou MJ, Chen FZ, Chen HC, et al.
ISG15 inhibits cancer cell growth and promotes apoptosis.
Int J Mol Med. 2017; 39(2):446-452 [PubMed] Related Publications
Cervical cancer is one of the most common causes of cancer-related mortality in women in developing countries. Interferon (IFN)-α has been widely used in the treatment of various types of cancer, including cervical cancer, and IFN-stimulated gene 15 (ISG15), an ubiquitin-like protein, is upregulated by IFN-α treatment. The anti-virus and antitumor effects of ISG15 have been reported; however, its mechanism of action have not yet been fully elucidated. In this study, HeLa cells were used as a model system to investigate the roles of ISG15 in IFN-α-mediated cancer cell growth inhibition and induction of apoptosis. The results revealed that both p53 and p21 were upregulated in HeLa cells treated with IFN-α or in the HeLa cells overexpressing ISG15. In addition, the expression levels of ubiquitin-like modifier-activating enzyme 7 (UBA7, also known as UBE1L; ISG15 E1-activating enzyme), UBCH8 (ISG15 E2-conjugating enzyme) and HERC5 (ISG15 E3-ligase) were elevated in the HeLa cells treated with IFN-α. The levels of p53 in the HeLa cells were attenuated by transient transfection with small interfering RNA (siRNA) targeting ISG15 (ISG15-siRNA). Cell viability was inhibited by both IFN-α treatment and ISG15 overexpression. However, these effects were significantly diminished when p53 was knocked down, suggesting that the effects of inhibitory effects of ISG15 on HeLa cell growth and the induction of apoptosis were p53-dependent. Taken together, these results suggest the existence of the IFN-α/ISG15/p53 axis in cervical cancer cells and any strategies manipulating the levels of ISG15 may thus prove to be effective in the treatment of cervical cancer.

Mustachio LM, Kawakami M, Lu Y, et al.
The ISG15-specific protease USP18 regulates stability of PTEN.
Oncotarget. 2017; 8(1):3-14 [PubMed] Free Access to Full Article Related Publications
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.

Yang Y, Zhang Y, Qu X, et al.
Identification of differentially expressed genes in the development of osteosarcoma using RNA-seq.
Oncotarget. 2016; 7(52):87194-87205 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Osteosarcoma (OS) is a malignant bone tumor with high morbidity in young adults and adolescents. This study aimed to discover potential early diagnosis biomarkers in OS.
RESULTS: In total, 111 differentially expressed genes (DEGs) were identified in primary OS compared with normal controls and 235 DEGs were identified in metastatic OS compared with primary OS. AURKB and PPP2R2B were the significantly up-regulated and down-regulated hub proteins, respectively, in the PPI protein-protein network (PPI) network of primary OS. ISG15 and BTRC were the significantly up-regulated and down-regulated hub proteins, respectively, in the network of metastatic OS. The DEGs in metastatic OS compared with primary OS were significantly enriched in the arachidonic acid metabolism, malaria, and chemokine signaling pathways. Finally, we employed quantitative real-time polymerase chain reaction (qRT-PCR) to validate the expression levels of candidate DEGs and the results indicated that our bioinformatics approach was acceptable.
MATERIALS AND METHODS: The mRNA expression profiling of 20 subjects was obtained through high-throughput RNA-sequencing. DEGs were identified between primary OS and normal Control, and between primary OS and metastatic OS, respectively. Functional annotation and PPI networks were used to obtain insights into the functions of DEGs. qRT-PCR was performed to detect the expression levels of dysregulated genes in OS.
CONCLUSIONS: Our work might provide groundwork for the further exploration of tumorigenesis and metastasis mechanisms of OS.

Mao H, Wang M, Cao B, et al.
Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway.
Oncotarget. 2016; 7(43):70143-70151 [PubMed] Free Access to Full Article Related Publications
Interferon-stimulated gene 15 (ISG15) is an important cytokine that has been reported in carcinogenesis. However, we found that ISG15 and de-ISGylase USP18 were induced by several anti-cancer agents, which was confirmed by both RT-PCR and immunoblotting assays. Further studies demonstrated that ectopic ISG15 and USP18 inhibited proliferation of myeloma, leukemia and cervical cancer cells. More importantly, ISG15 and USP18 induced cancer cell apoptosis. This finding was confirmed in a cervical xenograft model in which cervical cancer growth was suppressed by lentiviral ISG15. In the mechanistic study, ISG15 was found to disrupt the NF-κB signaling pathway by downregulating the expression of IKKβ and p65, phosphorylation of p65 and IκBα. Consistent with this finding, ISG15 suppressed the expression of NF-κB recognition element-driving luciferase and decreased the transcription of XIAP and Mcl-1, two typical genes regulated by NF-κB. Therefore, the present study demonstrated that ISG15 induces cancer cell apoptosis by disrupting the NF-κB signaling pathway. This study highlighted a novel role of ISG15 in tumor suppression.

Zuo C, Sheng X, Ma M, et al.
ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system.
Oncotarget. 2016; 7(45):74393-74409 [PubMed] Free Access to Full Article Related Publications
The interferon-stimulated gene 15 ubiquitin-like modifier (ISG15) encodes an IFN-inducible, ubiquitin-like protein. The ISG15 protein forms conjugates with numerous cellular proteins that are involved in a multitude of cellular functions, including interferon-induced immune responses and the regulation of cellular protein turnover. The expression of ISG15 and ISG15-mediated conjugation has been implicated in a wide range of human tumors and cancer cell lines, but the roles of ISG15 in tumorigenesis and responses to anticancer treatments remain largely unknown. In this review, we discuss the findings of recent studies with regard to the role of ISG15 pathways in cancers of the digestive system.

Hoan NX, Van Tong H, Giang DP, et al.
Interferon-stimulated gene 15 in hepatitis B-related liver diseases.
Oncotarget. 2016; 7(42):67777-67787 [PubMed] Free Access to Full Article Related Publications
This study investigates the association of Interferon-stimulated gene 15 (ISG15) polymorphisms, ISG15 serum levels and expression with HBV-related liver diseases. The ISG15 promoter and the two exons of the gene were screened for polymorphisms in 766 HBV-infected patients and in 223 controls. Soluble ISG15 levels were measured by ELISA. ISG15 mRNA expression was quantified by qRT-PCR in 36 tumor and adjacent non-tumor tissues. The exon 2 allele rs1921A was found associated with decreased progression of HBV-related liver diseases (LC vs. CHB: OR = 0.6, 95%CI = 0.4-0.8, adjusted P = 0.003; HCC vs. CHB: OR = 0.6, 95%CI = 0.4-0.9, adjusted P = 0.005). The rs1921AA genotype was associated with low levels of AST, ALT and total bilirubin, but with high prothrombin levels (P < 0.05). ISG15 serum levels were higher among HBV patients compared to controls (P < 0.0001) and positively associated with HBV-related liver diseases, with highest levels among LC patients. ISG15 levels were correlated with HBV-DNA loads (P = 0.001). In non-tumor tissues from HCC patients, ISG15 mRNA expression was increased in HBV compared to non-HBV infection (P = 0.016). The ISG15 rs1921 variant and ISG15 expression are associated with HBV-related liver diseases. Taken together, ISG15 appears to be a proviral factor involved in HBV replication and triggering progression of HBV-related liver diseases.

Park JH, Yang SW, Park JM, et al.
Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification.
Nat Commun. 2016; 7:12513 [PubMed] Free Access to Full Article Related Publications
p53 plays a pivotal role in tumour suppression under stresses, such as DNA damage. ISG15 has been implicated in the control of tumorigenesis. Intriguingly, the expression of ISG15, UBE1L and UBCH8 is induced by DNA-damaging agents, such as ultraviolet and doxorubicin, which are known to induce p53. Here, we show that the genes encoding ISG15, UBE1L, UBCH8 and EFP, have the p53-responsive elements and their expression is induced in a p53-dependent fashion under DNA damage conditions. Furthermore, DNA damage induces ISG15 conjugation to p53 and this modification markedly enhances the binding of p53 to the promoters of its target genes (for example, CDKN1 and BAX) as well as of its own gene by promoting phosphorylation and acetylation, leading to suppression of cell growth and tumorigenesis. These findings establish a novel feedback circuit between p53 and ISG15-conjugating system for positive regulation of the tumour suppressive function of p53 under DNA damage conditions.

Dai L, Bai L, Lin Z, et al.
Transcriptomic analysis of KSHV-infected primary oral fibroblasts: The role of interferon-induced genes in the latency of oncogenic virus.
Oncotarget. 2016; 7(30):47052-47060 [PubMed] Free Access to Full Article Related Publications
The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but the mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found within KS lesions, and KSHV can establish latent infection within human primary fibroblasts in vitro and in vivo, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. In the present study, we used Illumina microarray to determine global gene expression changes in KSHV-infected primary human oral fibroblasts (PDLF and HGF). Among significantly altered candidates, we found that a series of interferon-induced genes were strongly up-regulated in these KSHV-infected oral cells. Interestingly, some of these genes in particular ISG15 and ISG20 are required for maintenance of virus latency through regulation of specific KSHV microRNAs. Our data indicate that oral fibroblasts may represent one important host cellular defense component against viral infection, as well as acting as a reservoir for herpesvirus lifelong infection in the oral cavity.

Chen RH, Du Y, Han P, et al.
ISG15 predicts poor prognosis and promotes cancer stem cell phenotype in nasopharyngeal carcinoma.
Oncotarget. 2016; 7(13):16910-22 [PubMed] Free Access to Full Article Related Publications
Interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, is known for its anti-viral capacity. However, its role in tumorigenesis remains controversial. Here, using RNA-seq profiling analysis, we identified ISG15 as a differentially expressed gene in nasopharyngeal carcinoma (NPC) and validated its overexpression in NPC samples and cells. High ISG15 levels in NPC tissues were correlated with more frequent local recurrence and shorter overall survival and disease-free survival. ISG15 overexpression promoted a cancer stem cell phenotype in NPC cells, including increased colony and tumorsphere formation abilities, pluripotency-associated genes expression, and in vivo tumorigenicity. By contrast, knockdown of ISG15 attenuated stemness characteristics in NPC cells. Furthermore, overexpression of ISG15 increased NPC cell resistance to radiation and cisplatin (DDP) treatment. Our study demonstrates a protumor role of ISG15, and suggests that ISG15 is a prognostic predictor and a potential therapeutic target for NPC.

Hermann MR, Jakobson M, Colo GP, et al.
Integrins synergise to induce expression of the MRTF-A-SRF target gene ISG15 for promoting cancer cell invasion.
J Cell Sci. 2016; 129(7):1391-403 [PubMed] Related Publications
Integrin-mediated activation of small GTPases induces the polymerisation of G-actin into various actin structures and the release of the transcriptional co-activator MRTF from G-actin. Here we report that pan-integrin-null fibroblasts seeded on fibronectin and expressing β1- and/or αV-class integrin contained different G-actin pools, nuclear MRTF-A (also known as MKL1 or MAL) levels and MRTF-A-SRF activities. The nuclear MRTF-A levels and activities were highest in cells expressing both integrin classes, lower in cells expressing β1 integrins and lowest in cells expressing the αV integrins. Quantitative proteomics and transcriptomics analyses linked the differential MRTF-A activities to the expression of the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which is known to modify focal adhesion and cytoskeletal proteins. The malignant breast cancer cell line MDA-MB-231 expressed high levels of β1 integrins, ISG15 and ISGylated proteins, which promoted invasive properties, whereas non-invasive MDA-MB-468 and MCF-7 cell lines expressed low levels of β1 integrins, ISG15 and ISGylated proteins. Our findings suggest that integrin-adhesion-induced MRTF-A-SRF activation and ISG15 expression constitute a newly discovered signalling circuit that promotes cell migration and invasion.

Legrier ME, Bièche I, Gaston J, et al.
Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer.
Br J Cancer. 2016; 114(2):177-87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer.
METHODS: Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively.
RESULTS: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells.
CONCLUSIONS: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.

Tao J, Hua P, Wen J, et al.
Prognostic value of ISG15 mRNA level in drinkers with esophageal squamous cell cancers.
Int J Clin Exp Pathol. 2015; 8(9):10975-84 [PubMed] Free Access to Full Article Related Publications
ISG15, the protein encoded by interferon (IFN)-stimulated gene 15, was the first identified ubiquitin-like protein, which could be strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. Although the biological activities of ISG15 have yet to be fully elucidated, it is frequently overexpressed in various cancers. As the role of ISG15 in esophageal squamous cell cancer (ESCC) has not been well reported, the current study aimed to elucidate the role of ISG15 in predicting outcomes of ESCC patients. Samples were collected from 153 ESCC patients, including 54 pairs of tumor tissues and non-tumor tissues. Compared with the paired non-tumor tissues, higher expression of ISG15 mRNA were detected in ESCC tissues. The cut-off value 1.28 determined by ROC curve analysis divided the ESCC patients into high and low ISG15 mRNA expression group. High-ISG15 mRNA expression appeared with more frequency in ever-drinkers (P = 0.018). Kaplan-Meier analysis indicated that Low-ISG15 mRNA expression group had a longer cancer-specific survival (CSS) compared with High-ISG15 mRNA expression group. Multivariate analysis revealed that ISG15 mRNA (P = 0.024; hazard ratio, 2.759, 95% CI, 1.841-4.134) as well as Pathological staging (P < 0.001; hazard ratio, 1.634, 95% CI, 1.065-2.505) were independent prognostic factors. Subgroup analysis revealed that the discernibility of ISG15 mRNA level on ESCC outcomes was only pronounced in ever-drinkers (P = 0.026) not in never-drinkers (P = 0.138). ISG15 might serve as a novel prognostic biomarker in drinkers with ESCC.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. ISG15, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 01 September, 2019     Cancer Genetics Web, Established 1999