School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
Jiangxi Institute of Respiratory Disease, the First Affiliated Hospital of Nanchang University, Nanchang 330052, China.
Acta Biochim Biophys Sin (Shanghai). 2022 Nov 25;54(11):1610-1618. doi: 10.3724/abbs.2022160.
Abnormal proliferation and cell cycle perturbation are the main hallmarks of breast cancer. Cyclin-dependent kinase 1 (CDK1) is one of the key kinases for cell transition from the G2 phase to M phase during the cell cycle progression. However, little is known about the degradation mechanisms of CDK1. USP14 (ubiquitin-specific processing protease 14) is an important proteasome-associated deubiquitinase that is critical for proteome homeostasis and plays a crucial role in the initiation and development of cancer. In this study, we find that USP14 shows high expression in breast cancer cells and results in the abnormal proliferation of cancer cells. Furthermore, we examine cell cycle distribution by flow cytometry and find that inhibition of USP14 causes cell cycle arrest in G2/M phase. As CDK1 is the key kinase in G2/M phase, we detect the interaction between USP14 and CDK1 and the effect of USP14 on the deubiquitination of CDK1. The results reveal that USP14 interacts with CDK1 and stabilizes CDK1 by deubiquitinating K48-linked ubiquitination. In conclusion, our findings reveal an indispensable role of USP14 in regulating cell cycle progression by stabilizing CDK1 in breast cancer, suggesting that USP14 may be used as a potential therapeutic target in breast cancer therapy.
异常增殖和细胞周期紊乱是乳腺癌的主要特征。细胞周期蛋白依赖性激酶 1（CDK1）是细胞周期进展过程中细胞从 G2 期过渡到 M 期的关键激酶之一。然而，CDK1 的降解机制知之甚少。USP14（泛素特异性加工蛋白酶 14）是一种重要的蛋白酶体相关去泛素化酶，对蛋白质组稳态至关重要，并在癌症的发生和发展中发挥关键作用。在本研究中，我们发现 USP14 在乳腺癌细胞中高表达，导致癌细胞异常增殖。此外，我们通过流式细胞术检查细胞周期分布，发现抑制 USP14 会导致细胞周期停滞在 G2/M 期。由于 CDK1 是 G2/M 期的关键激酶，我们检测了 USP14 与 CDK1 的相互作用以及 USP14 对 CDK1 去泛素化的影响。结果表明，USP14 与 CDK1 相互作用，并通过去泛素化 K48 连接的泛素稳定 CDK1。总之，我们的研究结果揭示了 USP14 通过稳定 CDK1 在乳腺癌中调节细胞周期进程的不可或缺作用，提示 USP14 可能成为乳腺癌治疗的潜在治疗靶点。
