ISG15 in cancer: Beyond ubiquitin-like protein

Han, Hye Gyeong; Moon, Hye Won; Jeon, Young Joo

doi:10.1016/j.canlet.2018.09.007

Cited by 78 publications

(70 citation statements)

References 156 publications

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“…Up-regulation of ISG15 and increased ISGylation of target proteins are well-characterized IFN-mediated responses to pathogen infection (Perng and Lenschow, 2018) but are also associated with pathological conditions observed in many types of cancer. Depending on the context, either oncogenic or tumor suppressive effects were reported (Han et al, 2018). Here, we describe a novel unexpected function of the UBL ISG15 in the regulation of DNA synthesis.…”

Section: Accelerated Fork Progression By Isg15 Depends On the Functiomentioning

confidence: 92%

“…Overall, ISG15 function in regulating replication fork progression and genome stability contributes to explain the complex role of the IFN system, and of ISG15 itself, in tumorigenesis and cancer therapy (Han et al, 2018). A key challenge for future studies will be to understand if ISG15, via interaction or conjugation to protein partners, plays additional roles in the maintenance of genome integrity, impacting other fundamental aspects of DNA replication and/or the DNA damage response and repair, and whether its expression levels might be used to predict sensitivity to therapeutic treatments.…”

Section: Accelerated Fork Progression By Isg15 Depends On the Functiomentioning

confidence: 99%

“…Elevated levels of ISG15 expression occur in many types of cancer (Andersen et al, 2006;Bektas et al, 2008;Desai et al, 2006Desai et al, , 2012Ina et al, 2010;Jinawath et al, 2004;Laljee et al, 2013;Li et al, 2014;Padovan et al, 2002;Talvinen et al, 2006), and in some cases, the robust expression of ISG15 was reported to support tumor growth (Burks et al, 2014;Forys et al, 2014;Hadjivasiliou, 2012). In spite of the increasing interest on ISG15 and its clear correlation with human malignancies, its role in tumorigenesis is still controversial and largely unexplored (Han et al, 2018;Villarroya-Beltri et al, 2017), and its mechanism of action is far from being clarified.…”

Section: Introductionmentioning

confidence: 99%

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Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

Raso

Djoric

Walser

et al. 2020

Journal of Cell Biology

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DNA replication is highly regulated by the ubiquitin system, which plays key roles upon stress. The ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) is induced by interferons, bacterial and viral infection, and DNA damage, but it is also constitutively expressed in many types of cancer, although its role in tumorigenesis is still largely elusive. Here, we show that ISG15 localizes at the replication forks, in complex with PCNA and the nascent DNA, where it regulates DNA synthesis. Indeed, high levels of ISG15, intrinsic or induced by interferon-β, accelerate DNA replication fork progression, resulting in extensive DNA damage and chromosomal aberrations. This effect is largely independent of ISG15 conjugation and relies on ISG15 functional interaction with the DNA helicase RECQ1, which promotes restart of stalled replication forks. Additionally, elevated ISG15 levels sensitize cells to cancer chemotherapeutic treatments. We propose that ISG15 up-regulation exposes cells to replication stress, impacting genome stability and response to genotoxic drugs.

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Section: Accelerated Fork Progression By Isg15 Depends On the Functiomentioning

confidence: 92%

Section: Accelerated Fork Progression By Isg15 Depends On the Functiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

Raso

Djoric

Walser

et al. 2020

Journal of Cell Biology

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“…The expression of ISG15, and several other factors that regulate ISGylation, frequently exhibit dysregulation in different cancer types, but the mechanisms responsible for these effects and their outcomes are not clear, and may depend upon the cancer type. 34 Endosomes and mature MVBs are transported along microtubules by dynein/dynactin or kinesin motor complexes in a process regulated the activity of RAB family GTPases, with the inward movement of maturing endosomes regulated by the action of RAB5 and outward transport of mature MVBs regulated by RAB7A. 35 Evidence also suggests that RAB5 is involved in the regional enrichment of mitogenic receptors and exclusion of nutrient receptors, such as transferrin, which is removed from the maturing endosomes during dynein-mediated inward migration.…”

Section: Mvb Intracellular Transportmentioning

confidence: 99%

“…In this study, VPS23/tumor susceptibility gene 101 (TGS101) ISGylation was found to be sufficient to promote MVB degradation without altering ILV biogenesis, although the authors acknowledged that several proteins found in exosomes and MVBs are also potential ISGylation targets, including several ESCRT‐III complex subunits, and could thus contribute to an ISGylation‐mediated MVB degradation mechanism. The expression of ISG15, and several other factors that regulate ISGylation, frequently exhibit dysregulation in different cancer types, but the mechanisms responsible for these effects and their outcomes are not clear, and may depend upon the cancer type …”

Section: Introductionmentioning

confidence: 99%

Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail

Wan

Ning

Spiegel

et al. 2019

Medicinal Research Reviews

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Exosomes are abundantly secreted extracellular vesicles that accumulate in the circulation and are of great interest for disease diagnosis and evaluation since their contents reflects the phenotype of their cell of origin. Tumor‐derived exosomes (TDEs) are of particular interest for cancer diagnosis and therapy, since most tumor demonstrate highly elevated exosome secretion rates and provide specific information about the genotype of a tumor and its response to treatment. TDEs also contain regulatory factors that can alter the phenotypes of local and distant tissue sites and alter immune cell functions to promote tumor progression. The abundance, information content, regulatory potential, in vivo half‐life, and physical durability of exosomes suggest that TDEs may represent a superior source of diagnostic biomarkers and treatment targets than other materials currently under investigation. This review will summarize current information on mechanisms that may differentially regulate TDE biogenesis, TDE effects on the immune system that promote tumor survival, growth, and metastasis, and new approaches understudy to counteract or utilize TDE properties in cancer therapies.

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HnRNPA2B1 ISGylation Regulates m6A‐Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development

Jin,

Yang,

Chang

et al. 2024

Advanced Science

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Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no‐ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A‐modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon‐stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination‐mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A‐tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness‐related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A‐tagged mRNA associated with stemness maintenance, which suppresses BCSCs self‐renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A‐modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A‐tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy.

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ISG15 in cancer: Beyond ubiquitin-like protein

Cited by 78 publications

References 156 publications

Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail

HnRNPA2B1 ISGylation Regulates m6A‐Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development

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