Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer

Abstract

Background The deubiquitinating enzyme ubiquitin-specific protease 3 (USP3) plays a crucial role in numerous biological processes. The aberrant expression of USP3 may have an important role in tumor development. However, the mechanism by which USP3 promotes gastric cancer (GC) metastasis remains largely unknown. Methods Effects of USP3 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated utilizing proteomics, RT-PCR, western blotting, immunohistochemistry, immunofluorescence, cell invasion and migration assays and xenograft tumor models. Results USP3 expression was upregulated in GC compared with matched normal tissues and was predictive of poor survival. USP3 also promoted migration and epithelial-to-mesenchymal transition (EMT) in GC cells. Moreover, TGF-β1 induced USP3 expression, and USP3 knockdown inhibited TGF-β1-induced EMT. Furthermore, we utilized Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in USP3-overexpressing cells compared with control cells. Importantly, we found that SUZ12 is indispensable for USP3-mediated oncogenic activity in GC. We observed that USP3 interacted with and stabilized SUZ12 via deubiquitination. SUZ12 knockdown inhibited USP3-induced migration and invasion, as well as EMT in GC cells. Examination of clinical samples confirmed that USP3 expression was positively correlated with SUZ12 protein expression and that the levels of USP3 or SUZ12 protein were negatively correlated with the levels of E-cadherin protein. Conclusions These findings identify USP3 as a critical regulator. The USP3-SUZ12 axis might promote tumor progression and could be a potential therapeutic candidate for human GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1270-4) contains supplementary material, which is available to authorized users.

ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis

“…GC continues to be a highly lethal malignancy in spite of using varied treatment methods [19,20]. Hence, a better understanding of the mechanisms of GC proliferation is necessary [21].…”

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

“…It has also been reported that USP3 interacts with and stabilizes SUZ12 via deubiquitination. Expression of SUZ12 is negatively correlated with E-cadherin, which promotes migration and EMT in GC cells [95]. SMAD4 has been found to regulate EMT.…”

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

“…33 In addition, other studies have demonstrated that H3K27me3 levels in cancer cells are decreased concomitant with the reduction in the expression of suppressor of zeste 12 (SUZ12 protein homolog, a core component of PRC2), inhibiting the development of HCC and GC. 34,35 KMT2A (also called mixed lineage leukemia 1, MLL1) is another histone methyltransferase attracting increasing attention in digestive cancers. KMT2A functions by forming the MWRAD complex with WD repeat domain 5 (WDR5), RBBP5, ASH2L, and DPY30, 36 which possesses H3K4 methyltransferase activity and results in the installation of activating marks on chromatin at actively transcribed regions.…”

“… 33 In addition, other studies have demonstrated that H3K27me3 levels in cancer cells are decreased concomitant with the reduction in the expression of suppressor of zeste 12 (SUZ12 protein homolog, a core component of PRC2), inhibiting the development of HCC and GC. 34 , 35 …”