Ubiquitin-specific protease 3 facilitates cell proliferation by deubiquitinating pyruvate kinase L/R in gallbladder cancer

Liang, Ruopeng; Zhang, Xiaoxue; Zhao, Jie; Zhu, Ruijie; Wang, Weijie; Lu, Qin-Wei; Sun, Yuling

doi:10.1038/s41374-022-00836-1

Cited by 6 publications

(6 citation statements)

References 43 publications

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“…USP3, a deubiquitinating enzyme, affects tumor progression by participating in the regulation of multiple cellular activities [ 35 , 36 ]. USP3 promotes gallbladder cancer proliferation by modifying the deubiquitination level of pyruvate kinase L/R [ 37 ], and USP3 facilitates breast cancer progression through KLF5 deubiquitination [ 38 ]. Moreover, USP3 interacts with SUZ12 in gastric cancer and regulates the homeostasis of SUZ12 through deubiquitylation, thereby promoting the migration and invasion of gastric cancer cells [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

Li,

Wang,

Nie

et al. 2024

Cell Death Dis

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Ubiquitin-specific protease 3 (USP3) plays an important role in the progression of various tumors. However, the role of USP3 in osteosarcoma (OS) remains poorly understood. The aim of this study was to explore the biological function of USP3 in OS and the underlying molecular mechanism. We found that OS had higher USP3 expression compared with that of normal bone tissue, and high expression of USP3 was associated with poor prognosis in patients with OS. Overexpression of USP3 significantly increased OS cell proliferation, migration, and invasion. Mechanistically, USP3 led to the activation of the PI3K/AKT signaling pathway in OS by binding to EPHA2 and then reducing its protein degradation. Notably, the truncation mutant USP3-F2 (159–520) interacted with EPHA2, and amino acid 203 was found to play an important role in this process. And knockdown of EPHA2 expression reversed the pro-tumour effects of USP3-upregulating. Thus, our study indicates the USP3/EPHA2 axis may be a novel potential target for OS treatment.

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Section: Discussionmentioning

confidence: 99%

USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

Li,

Wang,

Nie

et al. 2024

Cell Death Dis

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“…USP3 is a nuclear DUB that primarily deubiquitylates and stabilizes targets for maintenance of genome stability, regulation of cell proliferation, DNA damage response, and the innate immune response. − There are currently no selective USP3 inhibitors due to the high conservation of the catalytic USP domain. The ZnF-UBD of USP3 is required for its interaction with and deubiquitylation of targets such as histone H2A and RIG-I. , …”

Section: Discussionmentioning

confidence: 99%

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle

Mann,

Wolf,

Silva

et al. 2023

ACS Omega

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Zinc-finger ubiquitin-binding domains (ZnF-UBDs) are noncatalytic domains mostly found in deubiquitylases (DUBs) such as USP3. They represent an underexplored opportunity for the development of deubiquitylase-targeting chimeras (DUBTACs) to pharmacologically induce the deubiquitylation of target proteins. We previously showed that ZnF-UBDs are ligandable domains. Here, a focused small molecule library screen against a panel of 11 ZnF-UBDs led to the identification of compound 59, a ligand engaging the ZnF-UBD of USP3 with a K D of 14 μM. The compound binds the expected C-terminal ubiquitin binding pocket of USP3 as shown by hydrogen–deuterium exchange mass spectrometry experiments and does not inhibit the cleavage of K48-linked diubiquitin by USP3. As such, this molecule is a chemical starting point toward chemical tools that could be used to interrogate the function of the USP3 Znf-UBD and the consequences of recruiting USP3 to ubiquitylated proteins.

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“…established gallbladder cancer (GBC) cell xenograft tumors by subcutaneously injecting GBC‐SD cells overexpressing USP3. The results indicated that tumor volume and size significantly increased with USP3 overexpression, while they decreased with USP3 knockdown 54 . Karapurkar et al.…”

Section: Animal Models Of Usp3mentioning

confidence: 91%

“…Consequently, this stabilization promotes cell proliferation, glycolysis, and tumor growth in vivo. 54 Notably, this marks the first instance of USP3 being implicated in tumor metabolism, although further investigation is warranted to fully understand the role of USP3 in this context.…”

Section: Ubiquitin‐specific Proteasementioning

confidence: 93%

USP3: Key deubiquitylation enzyme in human diseases

Zhang,

Liu,

et al. 2024

Cancer Science

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Ubiquitination and deubiquitylation are pivotal posttranslational modifications essential for regulating cellular protein homeostasis and are implicated in the development of human diseases. Ubiquitin‐specific protease 3 (USP3), a member of the ubiquitin‐specific protease family, serves as a key deubiquitylation enzyme, playing a critical role in diverse cellular processes including the DNA damage response, cell cycle regulation, carcinogenesis, tumor cell proliferation, migration, and invasion. Despite notable research efforts, our current understanding of the intricate and context‐dependent regulatory networks governing USP3 remains incomplete. This review aims to comprehensively synthesize existing published works on USP3, elucidating its multifaceted roles, functions, and regulatory mechanisms, while offering insights for future investigations. By delving into the complexities of USP3, this review strives to provide a foundation for a more nuanced understanding of its specific roles in various cellular processes. Furthermore, the exploration of USP3's regulatory networks may uncover novel therapeutic strategies targeting this enzyme in diverse human diseases, thereby holding promising clinical implications. Overall, an in‐depth comprehension of USP3's functions and regulatory pathways is crucial for advancing our knowledge and developing targeted therapeutic approaches for human diseases.

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Ubiquitin-specific protease 3 facilitates cell proliferation by deubiquitinating pyruvate kinase L/R in gallbladder cancer

Cited by 6 publications

References 43 publications

USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle

USP3: Key deubiquitylation enzyme in human diseases

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