Cargando…

NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma

INTRODUCTION: Melanoma is a common skin cancer that is usually associated with poor clinical outcomes. Recently, the immune checkpoint GITR has been identified as a promising target for immunotherapy of melanoma. In this study, we aimed to investigate the post-translational regulation mechanism of G...

Descripción completa

Detalles Bibliográficos
Autores principales: Guo, Yu, Yang, Lichang, Lei, Shaorong, Tan, Wuyuan, Long, Jianhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900405/
https://www.ncbi.nlm.nih.gov/pubmed/31824170
http://dx.doi.org/10.2147/OTT.S212317
_version_ 1783477351405846528
author Guo, Yu
Yang, Lichang
Lei, Shaorong
Tan, Wuyuan
Long, Jianhong
author_facet Guo, Yu
Yang, Lichang
Lei, Shaorong
Tan, Wuyuan
Long, Jianhong
author_sort Guo, Yu
collection PubMed
description INTRODUCTION: Melanoma is a common skin cancer that is usually associated with poor clinical outcomes. Recently, the immune checkpoint GITR has been identified as a promising target for immunotherapy of melanoma. In this study, we aimed to investigate the post-translational regulation mechanism of GITR in melanoma. METHODS: Western blotting was used to evaluate the protein expression of NEDD4, GITR and Foxp3. Real-time PCR (RT-PCR) was performed to determine expression levels of NEDD4, GITR, Foxp3 and IL-2. Cell viability was detected by MTT assay. The ubiquitination of GITR was evaluated by immunoprecipitation. NEDD4 expression data and melanoma survival data were obtained from The Cancer Genome Atlas (TCGA) and cBioPortal databases. RESULTS: We demonstrate that E3 ligase NEDD4 binds to GITR and mediates ubiquitination and degradation of GITR. Overexpression of NEDD4 inhibits anti-tumor immunity mediated by T cells against melanoma cells. We also found that the expression of NEDD4 is increased in metastatic melanoma. High NEDD4 expression level is correlated with the poor prognosis of melanoma patients. DISCUSSION: In summary, our findings demonstrated that E3 ligase NEDD4 mediates ubiquitination and degradation of GITR and suppresses T-cell-mediated-killings on melanoma cells. Our work highlighted the E3 ligase NEDD4 as a novel prognosis biomarker and therapeutic target for melanoma.
format Online
Article
Text
id pubmed-6900405
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Dove
record_format MEDLINE/PubMed
spelling pubmed-69004052019-12-10 NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma Guo, Yu Yang, Lichang Lei, Shaorong Tan, Wuyuan Long, Jianhong Onco Targets Ther Original Research INTRODUCTION: Melanoma is a common skin cancer that is usually associated with poor clinical outcomes. Recently, the immune checkpoint GITR has been identified as a promising target for immunotherapy of melanoma. In this study, we aimed to investigate the post-translational regulation mechanism of GITR in melanoma. METHODS: Western blotting was used to evaluate the protein expression of NEDD4, GITR and Foxp3. Real-time PCR (RT-PCR) was performed to determine expression levels of NEDD4, GITR, Foxp3 and IL-2. Cell viability was detected by MTT assay. The ubiquitination of GITR was evaluated by immunoprecipitation. NEDD4 expression data and melanoma survival data were obtained from The Cancer Genome Atlas (TCGA) and cBioPortal databases. RESULTS: We demonstrate that E3 ligase NEDD4 binds to GITR and mediates ubiquitination and degradation of GITR. Overexpression of NEDD4 inhibits anti-tumor immunity mediated by T cells against melanoma cells. We also found that the expression of NEDD4 is increased in metastatic melanoma. High NEDD4 expression level is correlated with the poor prognosis of melanoma patients. DISCUSSION: In summary, our findings demonstrated that E3 ligase NEDD4 mediates ubiquitination and degradation of GITR and suppresses T-cell-mediated-killings on melanoma cells. Our work highlighted the E3 ligase NEDD4 as a novel prognosis biomarker and therapeutic target for melanoma. Dove 2019-12-04 /pmc/articles/PMC6900405/ /pubmed/31824170 http://dx.doi.org/10.2147/OTT.S212317 Text en © 2019 Guo et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Guo, Yu
Yang, Lichang
Lei, Shaorong
Tan, Wuyuan
Long, Jianhong
NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma
title NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma
title_full NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma
title_fullStr NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma
title_full_unstemmed NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma
title_short NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma
title_sort nedd4 negatively regulates gitr via ubiquitination in immune microenvironment of melanoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900405/
https://www.ncbi.nlm.nih.gov/pubmed/31824170
http://dx.doi.org/10.2147/OTT.S212317
work_keys_str_mv AT guoyu nedd4negativelyregulatesgitrviaubiquitinationinimmunemicroenvironmentofmelanoma
AT yanglichang nedd4negativelyregulatesgitrviaubiquitinationinimmunemicroenvironmentofmelanoma
AT leishaorong nedd4negativelyregulatesgitrviaubiquitinationinimmunemicroenvironmentofmelanoma
AT tanwuyuan nedd4negativelyregulatesgitrviaubiquitinationinimmunemicroenvironmentofmelanoma
AT longjianhong nedd4negativelyregulatesgitrviaubiquitinationinimmunemicroenvironmentofmelanoma