USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer

Shi, Dongni; Wu, Xiao; Jian, Yunting; Wang, Junye; Huang, Chengmei; Mo, Shuang; Li, Yue; Li, Fengtian; Zhang, Chao; Zhang, Dongsheng; Zhang, Huizhong; Huang, Huilin; Chen, Xin; Wang, Y. Alan; Lin, Chuyong; Liu, Guozhen; Song, Libing; Liao, Wen Ting

doi:10.1038/s41467-022-33285-x

Cited by 75 publications

(47 citation statements)

References 70 publications

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“…According to earlier research, USP14 is crucial in sti ing antitumor immunity. (Shi et al 2022;Wang et al 2021) A review of the literature revealed no research investigating the molecular processes of carcinogenesis and development, as well as the potential diagnostic and prognostic utility of USP14. Therefore, a pan-cancer analysis of USP14 to explore its potential molecular mechanisms in different tumors is crucial and signi cant.…”

Section: Discussionmentioning

confidence: 99%

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A pan-cancer analysis of charged ubiquitin-specific protease 14's carcinogenic effects

2022

Preprint

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According to earlier research, the IDO1 protein is stabilized by overexpression of the ubiquitin-specific protease 14 (USP14), which increases tryptophan metabolism and T-cell failure. These results emphasize the function of USP14 in suppressing anti-tumor immunity and post-translational regulation in IDO1. USP14, however, does not have a Pan-cancer analysis. Using internet databases and R software, we looked at the possible oncogenic involvement of USP14 in 33 cancers using the TCGA and GEO datasets. We found fibroblast infiltration linked with malignancy in various cancers, including cervical squamous cell carcinoma, colon cancer, glioblastoma multiforme, and head and neck squamous cell carcinoma. The carcinogenic significance of USP14 in many malignancies is rather well understood because of the current pan-cancer investigation that we conducted.

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Section: Discussionmentioning

confidence: 99%

“…A rising number of studies have revealed that USP14 is implicated in a range of usual signaling pathways linked to cancer, neurological disorders, autophagy, immunological responses, and viral infections. (Shi et al 2022; Wang et al 2021) However, there is still no systematic pan-cancer analysis for USP14.…”

Section: Introductionmentioning

confidence: 99%

A pan-cancer analysis of charged ubiquitin-specific protease 14's carcinogenic effects

2022

Preprint

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“…For instance, tryptophan metabolism is a major metabolic pathway which restricts anti-tumor immunity and promotes intrinsic malignant properties of tumor cells, and considers as a target for cancer immunotherapy. 677 – 679 Tryptophan metabolism changes could result in a series of alterations in tumor microenvironment and tumor cells, and then promote tumor progression. Via hindering DNA repair, small molecule metabolites had accumulated in tumors involved in abnormal metabolism.…”

Section: Functional Targetmentioning

confidence: 99%

Small molecule metabolites: discovery of biomarkers and therapeutic targets

Qiu

Cai

et al. 2023

Sig Transduct Target Ther

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Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks of diseases. Metabolite signatures that have close proximity to subject’s phenotypic informative dimension, are useful for predicting diagnosis and prognosis of diseases as well as monitoring treatments. The lack of early biomarkers could lead to poor diagnosis and serious outcomes. Therefore, noninvasive diagnosis and monitoring methods with high specificity and selectivity are desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool for metabolic biomarker and pathway analysis, for revealing possible mechanisms of human various diseases and deciphering therapeutic potentials. It could help identify functional biomarkers related to phenotypic variation and delineate biochemical pathways changes as early indicators of pathological dysfunction and damage prior to disease development. Recently, scientists have established a large number of metabolic profiles to reveal the underlying mechanisms and metabolic networks for therapeutic target exploration in biomedicine. This review summarized the metabolic analysis on the potential value of small-molecule candidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening and treatment. We also discuss challenges that need to be addressed to fuel the next wave of breakthroughs.

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“…Interestingly, depletion of USP12 established a tumor-promoting TME due to insufficient deubiquitination of PPM1B and activation of NF-κB in cancer cells, which contributed to desensitization of anti-PD-1 immunotherapy in lung cancer cells ( 82 ). In addition, USP14 stabilized indoleamine 2,3 dioxygenase 1 (IDO1) and enhanced immune suppression in colorectal cancer ( 83 ). Depletion of USP14 promoted anti-PD-1 responsiveness in mice and reversed inhibition of cytotoxic T cells due to inhibition of IDOI ( 83 ).…”

Section: Deubiquitinases Stabilize Pd-1/pd-l1mentioning

confidence: 99%

“…In addition, USP14 stabilized indoleamine 2,3 dioxygenase 1 (IDO1) and enhanced immune suppression in colorectal cancer ( 83 ). Depletion of USP14 promoted anti-PD-1 responsiveness in mice and reversed inhibition of cytotoxic T cells due to inhibition of IDOI ( 83 ).…”

Section: Deubiquitinases Stabilize Pd-1/pd-l1mentioning

confidence: 99%

The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy

et al. 2023

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The tumor microenvironment (TME) is the tumor surrounding environment, which is critical for tumor development and progression. TME is also involved in clinical intervention and treatment outcomes. Modulation of TME is useful for improving therapy strategies. PD-L1 protein on tumor cells interacts with PD-1 protein on T cells, contributing to T cell dysfunction and exhaustion, blockage of the immune response. Evidence has demonstrated that the expression of PD-1/PD-L1 is associated with clinical response to anti-PD-1/PD-L1 therapy in cancer patients. It is important to discuss the regulatory machinery how PD-1/PD-L1 protein is finely regulated in tumor cells. In recent years, studies have demonstrated that PD-1/PD-L1 expression was governed by various E3 ubiquitin ligases in TME, contributing to resistance of anti-PD-1/PD-L1 therapy in human cancers. In this review, we will discuss the role and molecular mechanisms of E3 ligases-mediated regulation of PD-1 and PD-L1 in TME. Moreover, we will describe how E3 ligases-involved PD-1/PD-L1 regulation alters anti-PD-1/PD-L1 efficacy. Altogether, targeting E3 ubiquitin ligases to control the PD-1/PD-L1 protein levels could be a potential strategy to potentiate immunotherapeutic effects in cancer patients.

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USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer

Cited by 75 publications

References 70 publications

A pan-cancer analysis of charged ubiquitin-specific protease 14's carcinogenic effects

A pan-cancer analysis of charged ubiquitin-specific protease 14's carcinogenic effects

Small molecule metabolites: discovery of biomarkers and therapeutic targets

The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy

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