Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation

• Published in: Cell death & disease 2022-03, Vol.13 (3), p.231-12, Article 231
• Main Authors: Wu, Linhui, Yu, Ke, Chen, Kai, Zhu, Xuelian, Yang, Zheng, Wang, Qi, Gao, Junjie, Wang, Yingying, Cao, Tong, Xu, Hui, Pan, Xueshan, Wang, Lixia, Xia, Jun, Li, Yuyun, Wang, Zhiwei Peter, Ma, Jia
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 45/22; 45/29; 631/67/1504/1713; 692/699/1503/1712/1713; 82/80; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Cell Biology; Cell Culture; Cell viability; Conserved sequence; Ectopic expression; F-box protein; F-Box Proteins - genetics; F-Box Proteins - metabolism; Humans; Immunology; Kinases; Life Sciences; Mice; Molecular modelling; NIMA-Related Kinases - metabolism; Pancreatic cancer; Pancreatic carcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Polymerase chain reaction; Protein Binding; Transfection; Tumor suppressor genes; Tumorigenesis; Ubiquitin; Ubiquitin - metabolism; Ubiquitin Thiolesterase - metabolism; Ubiquitin-protein ligase; Ubiquitination; Western blotting; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04675-2

Fbxo45, a conserved F-box protein, comprises of an atypical SKP1, CUL1, F-box protein (SCF) ubiquitin ligase complex that promotes tumorigenesis and development. However, the biological function and molecular mechanisms of Fbxo45 involved in pancreatic carcinogenesis are ambiguous. We conducted several approaches, including transfection, coIP, real-time polymerase chain reaction (RT-PCR), Western blotting, ubiquitin assays, and animal studies, to explore the role of Fbxo45 in pancreatic cancer. Here, we report that USP49 stability is governed by Fbxo45-mediated ubiquitination and is enhanced by the absence of Fbxo45. Moreover, Fbxo45 binds to a short consensus sequence of USP49 through its SPRY domain. Furthermore, Fbxo45-mediated USP49 ubiquitination and degradation are enhanced by NEK6 kinase. Functionally, Fbxo45 increases cell viability and motility capacity by targeting USP49 in pancreatic cancer cells. Xenograft mouse experiments demonstrated that ectopic expression of Fbxo45 enhanced tumor growth in mice and that USP49 overexpression inhibited tumor growth in vivo. Notably, Fbxo45 expression was negatively associated with USP49 expression in pancreatic cancer tissues. Fbxo45 serves as an oncoprotein to facilitate pancreatic oncogenesis by regulating the stability of the tumor suppressor USP49 in pancreatic cancer.