Ubiquitin–proteasome system-targeted therapy for uveal melanoma: what is the evidence?

Zhao, Chenxi; Zeng, Chenming; Wang, Ke; He, Qiaojun; Yang, Bo; Zhou, Fanfan; Zhu, Hong

doi:10.1038/s41401-020-0441-3

Cited by 13 publications

(8 citation statements)

References 146 publications

(207 reference statements)

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“…The ubiquitin-proteasome system modulates the degradation of proteins which regulate the cell cycle and cell fate, including the tumour suppressor gene p53 and the proinflammatory signaling regulator NFjB [155,156].…”

Section: Proteasomal Inhibitorsmentioning

confidence: 99%

Development of new therapeutic options for the treatment of uveal melanoma

et al. 2021

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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies.Attempts to utilize the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors that are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualized tumour profiling. It would also be important to characterize UM tumours to differentiate the potential drivers of progression from those in other types of cancers.The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible. Accepted ArticleThis article is protected by copyright. All rights reserved A) Uveal Melanoma: Background and risk factors Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and represents ~5 % of melanoma diagnoses in the US annually [1-3]. UM originates from ocular melanocytes with 85% of cases arising from the choroid region and the remainder from the ciliary body and iris [4]. The prognosis in UM is poor, in particular because around 50% of patients develop metastatic disease. Hepatic metastases occur in up to 90% of individuals, followed by metastases in lung and bones, and after establishment of metastatic disease the median survival time is only 4-5 months [5]. At the time of diagnosis, systemic metastases are reported in only 3%of patients, but it is likely that micro-metastases have already developed in many cases [6,7].Currently there are no effective systemic drug therapies for primary or metastatic UM [8,9].The median age at diagnosis is 62 years and the incidence of UM in males and females, and whether there is right or left eye involvement, is similar [10]. Underlying risk factors for UM include melanocytosis, melanocytoma, neurofibromatosis and the presence of atypical nevi [11][12][13][14]. Race is also a significant risk factor with a 150-fold greater incidence in fair-skinned over dark-skinned populations [15]. The incidence of UM in European countries varies wi...

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Section: Proteasomal Inhibitorsmentioning

confidence: 99%

Development of new therapeutic options for the treatment of uveal melanoma

et al. 2021

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“…Moreover, glycosylation has the potential to act as a prognostic indicator, as a signature of glycosylation-related genes (GRGs) was shown to predict clinical outcomes in ovarian cancer patients ( 15 ). Other post-translational regulatory mechanisms, such as ubiquitination ( 16 ), phosphorylation ( 17 ) and epigenetic modifications ( 18 ) have also been reported as potential biomarkers in UM prognostic models. However, despite being one of the most crucial post-transcriptional alterations among the 300 protein modifications, few studies have explored the relationship between GRGs signature and the tumor microenvironment (TME) of UM.…”

Section: Introductionmentioning

confidence: 99%

Integrating single-cell analysis and machine learning to create glycosylation-based gene signature for prognostic prediction of uveal melanoma

et al. 2023

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BackgroundIncreasing evidence suggests a correlation between glycosylation and the onset of cancer. However, the clinical relevance of glycosylation-related genes (GRGs) in uveal melanoma (UM) is yet to be fully understood. This study aimed to shed light on the impact of GRGs on UM prognosis.MethodsTo identify the most influential genes in UM, we employed the AUCell and WGCNA algorithms. The GRGs signature was established by integrating bulk RNA-seq and scRNA-seq data. UM patients were separated into two groups based on their risk scores, the GCNS_low and GCNS_high groups, and the differences in clinicopathological correlation, functional enrichment, immune response, mutational burden, and immunotherapy between the two groups were examined. The role of the critical gene AUP1 in UM was validated through in vitro and in vivo experiments.ResultsThe GRGs signature was comprised of AUP1, HNMT, PARP8, ARC, ALG5, AKAP13, and ISG20. The GCNS was a significant prognostic factor for UM, and high GCNS correlated with poorer outcomes. Patients with high GCNS displayed heightened immune-related characteristics, such as immune cell infiltration and immune scores. In vitro experiments showed that the knockdown of AUP1 led to a drastic reduction in the viability, proliferation, and invasion capability of UM cells.ConclusionOur gene signature provides an independent predictor of UM patient survival and represents a starting point for further investigation of GRGs in UM. It offers a novel perspective on the clinical diagnosis and treatment of UM.

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“…With the development of basic and clinical research, scientists are now increasingly aware of the underlying molecular mechanisms that give rise to UVM [ 11 ]. Targeted therapies and immunotherapies that mainly focus on the advanced stages of UVM are on the way [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Single cell sequencing analysis constructed the N7-methylguanosine (m7G)-related prognostic signature in uveal melanoma

Xie

Chen

Cao

et al. 2023

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Background: Uveal melanoma is a highly malignant tumor in the eye. Its recurrence and metastasis are common, and the prognosis is poor. Methods: The transcriptome data of UVM were downloaded from TCGA database, and the single cell sequencing dataset GSE139829 was downloaded from GEO database. Weighted co-expression network analysis was used to explore the modules associated with m7G. Lasso regression was used to construct M 7 G-related prognostic signature. Immune infiltration analysis was used to explore the significance of the model in the tumor immune microenvironment. Finally, cell assays were used to explore the function of key genes in the MUM-2B and OCM-1 cell lines of UVM. Results: The prognostic signature was constructed by Cox regression and Lasso regression. Patients could be divided into high-risk group and low-risk group by this signature, and the high-risk group had worse prognosis (P<0.05). Cell experiments showed that the proliferation, invasion and migration ability of UVM cell lines were significantly decreased after the knockdown of PAG1, a key gene in signature, which proved that PAG1 might be a potential target of UVM. Conclusions: Our study explored the significance of m 7 G in UVM, provided biomarkers for its diagnosis and treatment.

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Ubiquitin–proteasome system-targeted therapy for uveal melanoma: what is the evidence?

Cited by 13 publications

References 146 publications

Development of new therapeutic options for the treatment of uveal melanoma

Development of new therapeutic options for the treatment of uveal melanoma

Integrating single-cell analysis and machine learning to create glycosylation-based gene signature for prognostic prediction of uveal melanoma

Single cell sequencing analysis constructed the N7-methylguanosine (m7G)-related prognostic signature in uveal melanoma

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