Review Article

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

Chen-xi Zhao1, Chen-ming Zeng1, Ke Wang2, Qiao-jun He1, Bo Yang1, Fan-fan Zhou3, Hong Zhu1
1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China
3 Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2050, Australia
Correspondence to: Fan-fan Zhou:, Hong Zhu:,
DOI: 10.1038/s41401-020-0441-3
Received: 8 March 2020
Accepted: 12 May 2020
Advance online: 29 June 2020


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.
Keywords: Uveal melanoma; BAP1; ubiquitin–proteasome system; DUB; molecular targeted therapy

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