Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Mustachio, Lisa Maria; Lu, Yun; Kawakami, Masanori; Roszik, Jason; Freemantle, Sarah J.; Liu, Xi; Dmitrovsky, Ethan

doi:10.1158/0008-5472.can-17-1752

Cited by 41 publications

(41 citation statements)

References 50 publications

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“…Furthermore, the relationship between USP18 DNA hypomethylated and USP18 RNA ac 4 C hyperacetylated in SLE should be explored in the future. It has been reported that engineered gain of USP18 decreases cancer growth by destabilizing growth-regulatory proteins ( Mustachio et al, 2018 ), which suggests that USP18 may alter transcribed mRNA catabolic process and translational initiation to facilitate the pathogenesis of SLE. In contrast, a previous study has discovered that the engineered loss of USP18 increases ISGylation ( François-Newton et al, 2011 ); therefore, upregulated USP18 might reduce ISGylation to inactivate the interferon response, implying the function of ac 4 C modification in SLE which should be identified in further studies.…”

Section: Discussionmentioning

confidence: 99%

Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Guo

Shi

Wang

et al. 2020

Front. Cell Dev. Biol.

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The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (ac 4 C) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA ac 4 C modification are involved in systemic lupus erythematosus (SLE) remains unclear. Herein, we detected eleven modifications in CD4 + T cells of SLE patients using mass spectrometry (LC-MS/MS). Furthermore, using samples from four CD4 + T cell pools, we identified lower modification of ac 4 C mRNA in SLE patients as compared to that in healthy controls (HCs). Meanwhile, significantly lower mRNA acetyltransferase NAT10 expression was detected in lupus CD4 + T cells by RT-qPCR. We then illustrated the transcriptome-wide ac 4 C profile in CD4 + T cells of SLE patients by ac 4 C-RIP-Seq and found ac 4 C distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 ac 4 C hyper-acetylated and hypoacetylated peaks found in SLE samples, respectively, were found to be significantly involved in SLE-related function enrichments, including multiple metabolic and transcription-related processes, ROSinduced cellular signaling, apoptosis signaling, and NF-κB signaling. Moreover, we demonstrated the ac 4 C-modified regulatory network of gene biological functions in lupus CD4 + T cells. Notably, we determined that the 26 upregulated genes with hyperacetylation played essential roles in autoimmune diseases and disease-related processes. Additionally, the unique ac 4 C-related transcripts, including USP18, GPX1, and RGL1, regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated ac 4 C mRNAs associated with critical immune and inflammatory responses, that have translational potential in lupus CD4 + T cells. Hence, our findings reveal transcriptional significance and potential therapeutic targets of mRNA ac 4 C modifications in SLE pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Guo

Shi

Wang

et al. 2020

Front. Cell Dev. Biol.

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“…A recent study highlighted the requirement to target negative regulators like the ISGs, SOCS1 and SOCS3 and identified a natural compound 6-hydroxy-3- O -methyl-kaempferol 6- O -glucopyranoside (K6G) which inhibited SOCS3 expression and stimulated type I IFN induced ISRE reporter expression ( 138 ). There is also strong evidence that USP18 is worth pursuing as a promising target and recent advances in solving its crystal structure along with ISG15 should help make this idea a reality in the clinic ( 139 ). On the other hand, an IRF inhibitor, LY294002, which targets IFN-β production via IRF3 inhibition ( 140 ), has been shown to sensitize cancer cells to chemotherapy in cervical cancer cells by enhancing mitochondrial JNK signaling.…”

Section: Targeting Type I Ifn Signaling Pathway As a Promising Stratementioning

confidence: 99%

Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance

2018

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The efficacy of several therapeutic strategies against cancer, including cytotoxic drugs, radiotherapy, targeted immunotherapies and oncolytic viruses, depend on intact type I interferon (IFN) signaling for the promotion of both direct (tumor cell inhibition) and indirect (anti-tumor immune responses) effects. Malfunctions of this pathway in tumor cells or in immune cells may be responsible for the lack of response or resistance. Although type I IFN signaling is required to trigger anti-tumor immunity, emerging evidence indicates that chronic activation of type I IFN pathway may be involved in mediating resistance to different cancer treatments. The plastic and dynamic features of type I IFN responses should be carefully considered to fully exploit the therapeutic potential of strategies targeting IFN signaling. Here, we review available evidence supporting the involvement of type I IFN signaling in mediating resistance to various cancer therapies and highlight the most promising modalities that are being tested to overcome resistance.

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“…ISGylation is reversible through the deconjugating activity of USP18 [52] , [53] . USP18 transcripts were not increased in mt BRCA1 samples at baseline and emerged as significantly elevated only after FF exposure, when HERC5 transcripts were also elevated.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells

et al. 2018

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Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC.

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Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Cited by 41 publications

References 50 publications

Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells

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