&lt;p&gt;NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma&lt;/p&gt;

Guo, Yu; Yang, Lizhen; Lei, Shaorong; Tan, Wuyuan; Long, Junling

doi:10.2147/ott.s212317

Cited by 20 publications

(19 citation statements)

References 36 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An increased production of the TRAIL-ligand TNFSF10 along with a decrease of the decoy receptor TNFRSF10c ( Pan et al, 1997 ) suggest that additional factors to DR5 could contribute to the improved apoptosis susceptibility of FKBP51-targeted melanoma cells. Also, according to a recent study, TNFRSF18/GITR enhances T cell-mediated killing of melanoma cells ( Guo et al, 2019 ). The observation that this immune checkpoint molecule ( Ronchetti et al, 2004 ) is apparently upregulated in FKBP51-depleted cells is a further element in support that melanoma microenvironment can benefit from FKBP51 targeting.…”

Section: Discussionmentioning

confidence: 96%

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

Tufano

Cesaro

Martinelli

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.

show abstract

Section: Discussionmentioning

confidence: 96%

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

Tufano

Cesaro

Martinelli

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Melanoma is the most invasive type of skin cancer with a challenge to identify prognostic biomarkers. As a cancer largely regulated by immune system, the development of immune-related biomarkers would be of much value [36][37][38] . And prediction model for prognosis based on multiple markers including immune genes would potentially help with selecting the optimal therapy in the clinic.…”

Section: Discussionmentioning

confidence: 99%

A novel predictive model incorporating immune-related gene signatures for overall survival in melanoma patients

Liao

Zeng

Yao

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Melanoma is the most invasive type of skin cancer, in which the immune system plays a vital role. In this study, we aimed to establish a prognostic prediction nomogram for melanoma patients that incorporates immune-related genes (IRGs). Ninety-seven differentially expressed IRGs between melanoma and normal skin were screened using gene expression omnibus database (GEO). Among these IRGs, a two-gene signature consisting of CCL8 and DEFB1 was found to be closely associated with patient prognosis using the cancer genome atlas (TCGA) database. Survival analysis verified that the IRGs score based on the signature gene expressions efficiently distinguished between high-and low-risk patients, and was identified to be an independent prognostic factor. A nomogram integrating the IRGs score, age and TNM stage was established to predict individual prognosis for melanoma. The prognostic performance was validated by the TCGA/GEO-based concordance indices and calibration plots. The area under the curve demonstrated that the nomogram was superior than the conventional staging system, which was confirmed by the decision curve analysis. Overall, we developed and validated a nomogram for prognosis prediction in melanoma based on IRGs signatures and clinical parameters, which could be valuable for decision making in the clinic. Abbreviations PD-1 Programmed death-1 CLTA-4 Cytotoxic T-lymphocyte antigen 4 GEO Gene expression omnibus TCGA The cancer genome atlas DEGs Differentially expressed genes IRGs Immune-related genes DE-IRGs Differentially expressed immune-related genes KEGG Kyoto encyclopedia of genes and genomes GO Gene ontology PPI Protein-protein interactions LASSO Least absolute shrinkage and selection operator OS Overall survival GEPIA Gene expression profiling interactive analysis ROC Receiver operating characteristic AUC Area under the curve DCA Decision curve analysis HR Hazard ratio

show abstract

“…The E3 ligase NEDD4 mediates ubiquitination and degradation of GITR and negatively regulates T cell-mediated antitumor immunity. 112 Roquin 1 (Rc3h1) and its paralog Roquin 2 (Rc3h2), E3 ubiquitin ligases and RNA binding proteins, repress the expression of OX40, as well as the CD28 family costimulatory receptor ICOS, by promoting degradation of their mRNAs. 113 – 115 Roquins play a crucial role in regulating differentiation of Tfh cells and pathogenesis of autoimmune and inflammatory diseases, but it is unclear whether they also play a role in regulating antitumor immunity.…”

Section: Costimulatory and Coinhibitory Signalingmentioning

confidence: 99%

Targeting ubiquitin signaling for cancer immunotherapy

Zhou

Sun

2021

Sig Transduct Target Ther

View full text Add to dashboard Cite

Cancer immunotherapy has become an attractive approach of cancer treatment with tremendous success in treating various advanced malignancies. The development and clinical application of immune checkpoint inhibitors represent one of the most extraordinary accomplishments in cancer immunotherapy. In addition, considerable progress is being made in understanding the mechanism of antitumor immunity and characterizing novel targets for developing additional therapeutic approaches. One active area of investigation is protein ubiquitination, a post-translational mechanism of protein modification that regulates the function of diverse immune cells in antitumor immunity. Accumulating studies suggest that E3 ubiquitin ligases and deubiquitinases form a family of potential targets to be exploited for enhancing antitumor immunity in cancer immunotherapy.

show abstract

<p>NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma</p>

Cited by 20 publications

References 36 publications

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

A novel predictive model incorporating immune-related gene signatures for overall survival in melanoma patients

Targeting ubiquitin signaling for cancer immunotherapy

Contact Info

Product

Resources

About