Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical College, Bengbu, Anhui, 233030, China.
Department of Laboratory Medicine, School of Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui, 233030, China.
Cell Death Dis. 2022 Mar 12;13(3):231. 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.
Fbxo45 是一种保守的 F-box 蛋白，它由一个非典型的 SKP1、CUL1、F-box 蛋白 (SCF) 泛素连接酶复合物组成，该复合物促进肿瘤的发生和发展。然而，Fbxo45 在胰腺发生癌变过程中的生物学功能和分子机制尚不清楚。我们通过转染、coIP、实时聚合酶链反应 (RT-PCR)、Western blot、泛素测定和动物研究等几种方法，探索了 Fbxo45 在胰腺癌中的作用。在这里，我们报告 USP49 的稳定性受 Fbxo45 介导的泛素化调控，并且在缺乏 Fbxo45 时会增强。此外，Fbxo45 通过其 SPRY 结构域与 USP49 的短共有序列结合。此外，Fbxo45 介导的 USP49 泛素化和降解通过 NEK6 激酶增强。功能上，Fbxo45 通过在胰腺癌细胞中靶向 USP49 增加细胞活力和迁移能力。异种移植小鼠实验表明，Fbxo45 的异位表达增强了小鼠体内的肿瘤生长，而 USP49 的过表达抑制了体内肿瘤的生长。值得注意的是，Fbxo45 的表达与胰腺癌细胞中 USP49 的表达呈负相关。Fbxo45 作为一种癌蛋白，通过调节肿瘤抑制因子 USP49 的稳定性，促进胰腺癌的发生。
