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Ubiquitin-proteasome system-targeted therapy for uveal melanoma: what is the evidence?
Chen-Xi Zhao1, Chen-Ming Zeng1, Ke Wang2
1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Abstract:
Uveal melanoma (UM) is a rare ocular tumor. The loss of BRCA1-associated protein 1 (BAP1) and the aberrant activation of G protein subunit alpha q (GNAQ)/G protein subunit alpha 11 (GNA11) contribute to the frequent metastasis of UM. Thus far, limited molecular-targeted therapies have been developed for the clinical treatment of UM. However, an increasing number of studies have revealed the close relationship between the ubiquitin proteasome system (UPS) and the malignancy of UM. UPS consists of a three-enzyme cascade, i.e. ubiquitin-activating enzymes (E1s); ubiquitin-conjugating enzymes (E2s); and ubiquitin-protein ligases (E3s), as well as 26S proteasome and deubiquitinases (DUBs), which work coordinately to dictate the fate of intracellular proteins through regulating ubiquitination, thus influencing cell viability. Due to the critical role of UPS in tumors, we here provide an overview of the crosstalk between UPS and the malignancy of UM, discuss the current UPS-targeted therapies in UM and highlight its potential in developing novel regimens for UM.
Insights
The ubiquitin proteasome system (UPS) is closely linked to uveal melanoma (UM) malignancy. Targeting UPS components offers potential for novel molecular therapies against this rare ocular tumor.
Area of Science:
- Oncology
- Molecular Biology
- Ophthalmology
Background:
- Uveal melanoma (UM) is a rare eye cancer with limited targeted therapies.
- Loss of BRCA1-associated protein 1 (BAP1) and aberrant GNAQ/GNA11 activation are key in UM metastasis.
- The ubiquitin proteasome system (UPS) regulates intracellular protein fate and is implicated in tumor progression.
Purpose of the Study:
- To review the relationship between the UPS and UM malignancy.
- To discuss current UPS-targeted therapies for UM.
- To highlight the potential of UPS modulation for novel UM treatment strategies.
Main Methods:
- Literature review focusing on the ubiquitin proteasome system (UPS) and uveal melanoma (UM).
- Analysis of studies detailing the role of UPS components (E1s, E2s, E3s, 26S proteasome, DUBs) in UM.
- Examination of existing and potential UPS-targeted therapeutic approaches in UM.
Main Results:
- The UPS plays a critical role in the biological processes driving UM malignancy.
- Dysregulation of ubiquitination pathways is a hallmark of UM.
- Several UPS components are potential targets for therapeutic intervention in UM.
Conclusions:
- The UPS is intricately involved in the development and progression of uveal melanoma.
- Targeting the UPS presents a promising avenue for developing novel molecular therapies for UM.
- Further research into UPS modulation could lead to effective treatment regimens for this ocular tumor.
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