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

• Published in: Cell death & disease 2021-12, Vol.13 (1), p.10-11, Article 10
• Main Authors: Wu, Xiaosheng, Wang, Hao, Zhu, Danping, Chai, Yixia, Wang, Jing, Dai, Weiyu, Xiao, Yizhi, Tang, Weimei, Li, Jiaying, Hong, Linjie, Pei, Miaomiao, Zhang, Jieming, Lin, Zhizhao, Wang, Jide, Li, Aimin, Liu, Side
• Format: Article
• Language: English
• Subjects: 13/1; 13/105; 13/51; 14/63; 38/79; 42/109; 631/337/458/582; 631/67/1504/1829; 64/60; 82/29; 82/80; 82/81; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Collagen (type IX); Collagen Type IX - genetics; Collagen Type IX - metabolism; Collagen Type VI - genetics; Collagen Type VI - metabolism; Disease Models, Animal; Enzymatic activity; Enzymes; Gastric cancer; Guanylate cyclase; Heterografts; Humans; Immunology; Life Sciences; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Metastases; Metastasis; Mice; Mice, Nude; Neoplasm Transplantation - methods; RNA Interference; Signal Transduction - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Therapeutic targets; Transfection - methods; Tumors; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; Ubiquitination - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04460-7

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.