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

• Published in: Journal of experimental & clinical cancer research Vol. 38; no. 1; p. 277
• Main Authors: Wu, Xiaosheng, Liu, Mengwei, Zhu, Huiqiong, Wang, Jing, Dai, Weiyu, Li, Jiaying, Zhu, Danping, Tang, Weimei, Xiao, Yizhi, Lin, Jianjiao, Zhang, Wenjing, Sun, Yong, Zhang, Yi, Chen, Yaying, Li, Guoxin, Li, Aimin, Xiang, Li, Liu, Side, Wang, Jide
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24-06-2019; BioMed Central; BMC
• Subjects: Animals; Cadherins - metabolism; Carcinoma - pathology; Carcinoma - secondary; Care and treatment; Cell Line, Tumor; Cell Movement; Development and progression; EMT; Epithelial-Mesenchymal Transition; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Humans; Immunohistochemistry; iTRAQ; Male; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Polycomb Repressive Complex 2 - biosynthesis; Polycomb Repressive Complex 2 - metabolism; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; SUZ12; Transforming Growth Factor beta1 - metabolism; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; Ubiquitination; Up-Regulation; USP3; Xenograft Model Antitumor Assays; SUZ12; iTRAQ; EMT; Gastric cancer; USP3
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-019-1270-4

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.
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.
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.
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.