Abstract
As an important regulator of intracellular protein degradation, the mechanism of the deubiquitinating enzyme family in tumour metastasis has received increasing attention. Our previous study revealed that USP3 promotes tumour progression and is highly expressed in gastric cancer (GC). Herein, we report two critical targets, COL9A3 and COL6A5, downstream of USP3, via the isobaric tags for relative and absolute quantification technique. Mechanistically, we observed that USP3 interacted with and stabilised COL9A3 and COL6A5 via deubiquitination in GC. Importantly, we found that COL9A3 and COL6A5 were essential mediators of USP3-modulated oncogenic activity in vitro and in vivo. Examination of clinical samples confirmed that elevated expression of USP3, concomitant with increased COL9A3 and COL6A5 abundance, correlates with human GC progression. These data suggest that USP3 promotes GC progression and metastasis by deubiquitinating COL9A3 and COL6A5. These findings identify a mechanism of GC metastasis regarding USP3-mediated deubiquitinating enzyme activity and suggest potential therapeutic targets for GC management.
Highlights
The incidence of gastric cancer (GC) has declined in recent years, it remains the fifth most common malignancy and the fourth leading cause of cancer-related deaths worldwide [1]
In a previous study, we have reported that Ubiquitin-specific protease 3 (USP3), as an important oncogene, is overexpressed in GC, promotes cell epithelial-tomesenchymal transition (EMT), migration and invasion in vitro and in vivo, and is associated with poor prognosis in GC patients [14]
We found that USP3 could interact with, deubiquitylate, and stabilise COL9A3 and COL6A5, thereby upregulating the protein expression of COL9A3 and COL6A5
Summary
The incidence of gastric cancer (GC) has declined in recent years, it remains the fifth most common malignancy and the fourth leading cause of cancer-related deaths worldwide [1]. A proportion of patients will eventually succumb to the disease as a result of metastasis due to missing the chance of curative surgery and leading to unsuccessful treatment in clinical settings [4]. Understanding the complex intrinsic mechanism of GC metastasis, mining promising molecular markers, and providing therapeutic targets for the early prevention, diagnosis, and treatment of GC metastasis is of great importance for improving the clinical outcome and prognosis of GC patients. USP3 has served as a deubiquitinase of Cdc25A and accelerated tumour proliferation, resulting in poor prognosis in patients with breast cancer [13]. Several studies have reported the altered expression and preliminary functions of USP3 in GC, existing findings regarding the driver role of USP3 and its detailed downstream targets in GC are limited; further studies are required to provide more evidence supporting USP3 as an essential oncogene in GC and further insights on the complex regulatory network of USP3mediated deubiquitination
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