USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation

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.

Identification of a minimum number of genes to predict triple-negative breast cancer subgroups from gene expression profiles

“…The latter operates by facilitating cancer cell growth and invasion by controlling E-cadherin-Src signalling and cell–cell adhesion. The same goes for COL9A3 [ 47 ], which is involved in matrix synthesis and controls its degradation. It was also identified as significantly associated with the prognosis of TNBC in an independent prognostic signature [ 48 ].…”

Deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners

“…Because HIV-1 Vif antagonizes A3G antiviral function by forming viral-specific cullin 5-RING ligase (CRL5) E3 ubiquitin ligase to promote the polyubiquitination and degradation of A3G, [ 5 , 52 , 53 ] we next determined whether the loss or gain of USP3 affected A3G expression in the presence of Vif. We found that increasing the level of USP3 expression effectively inhibited HIV-1 Vif-induced A3G degradation [Figure 1 G], while silencing endogenous USP3 enhanced it [Figure 1 H].…”

“…Studies have shown that USP3 plays a crucial role in numerous biological processes by deubiquitinating some host factors [54,66–70] . For example, USP3 regulates cancer progression and metastasis by deubiquitinating the Kruppel-like factor 5 (KLF5), stabilizing p53 or deubiquitination-dependent COL9A3/COL6A5 [53,71,72] . USP3 has also been identified as a novel regulator of histone H2A and H2B ubiquitination, highlighting its role in preventing replication stress and suggesting its involvement in the response to DNA double-strand breaks [55,70] .…”

Research Progress for Targeting Deubiquitinases in Gastric Cancers

“…Wu et al identified differentially expressed proteins in BGC-823 cells stably expressing USP3 [ 21 ]. Among them, SUZ12, a scaffolding component of the PRC2 complex, and COL9A3/COL6A5, collagen family members, were deubiquitinated and stabilized by USP3, which accounts for its role in promoting invasion and migration [ 21 , 22 ]. In addition to SUZ12, the core PRC2 complex also comprises the histone methyltransferase EZH2 and the scaffolding component EED.…”