The reversible post-translational modifications of protein ubiquitination and deubiquitination play a crucial regulatory role in cellular homeostasis. Deubiquitinases (DUBs) are responsible for the removal of ubiquitin from the protein substrates. The dysregulation of the DUBs may give rise to the occurrence and development of tumors. In this study, we investigated the gastric cancer (GC) data from the TCGA and GEO databases and found that ubiquitin-specific protease USP13 was significantly up-regulated in GC samples. The higher expression of USP13 was associated with the worse prognosis and shorter overall survival (OS) of GC patients. Enforced expression of USP13 in GC cells promoted the cell cycle progression and cell proliferation in an enzymatically dependent manner. Conversely, suppression of USP13 led to GC cell cycle arrest in G1 phase and the inhibition of cell proliferation. Nude mouse experiments indicated that depletion of USP13 in GC cells dramatically suppressed tumor growth in vivo. Mechanistically, USP13 physically bound to the N-terminal domain of cyclin D1 and removed its K48- but not K63-linked polyubiquitination chain, thereby stabilizing and increasing cyclin D1. Furthermore, re-expression of cyclin D1 partially reversed the cell cycle arrest and cell proliferation inhibition induced by USP13 depletion in GC cells. Additionally, USP13 protein abundance was positively correlated with the protein level of cyclin D1 in human GC tissues. Taken together, our data demonstrate that USP13 deubiquitinates and stabilizes cyclin D1, thereby promoting cell cycle progression and cell proliferation in GC. These findings suggest that USP13 might be a promising therapeutic target for the treatment of GC.

蛋白质泛素化和去泛素化的可逆翻译后修饰在细胞稳态中发挥着至关重要的调节作用。去泛素酶 (DUB) 负责从蛋白质底物中去除泛素。DUBs的失调可能导致肿瘤的发生和发展。在这项研究中，我们调查了TCGA和GEO数据库中的胃癌（GC）数据，发现泛素特异性蛋白酶USP13在GC样本中显着上调。USP13的高表达与GC患者的预后较差和总生存期(OS)较短相关。USP13 在 GC 细胞中的强制表达以酶依赖性方式促进细胞周期进展和细胞增殖。反过来，USP13 的抑制导致 GC 细胞周期停滞在 G1 期并抑制细胞增殖。裸鼠实验表明，GC 细胞中 USP13 的缺失可显着抑制体内肿瘤生长。从机制上讲，USP13 物理结合到细胞周期蛋白 D1 的 N 端结构域，并去除其 K48 连接的多泛素化链，但不去除 K63 连接的多聚泛素化链，从而稳定和增加细胞周期蛋白 D1。此外，cyclin D1 的重新表达部分逆转了 GC 细胞中 USP13 缺失引起的细胞周期停滞和细胞增殖抑制。此外，USP13蛋白丰度与人GC组织中cyclin D1的蛋白水平呈正相关。综上所述，我们的数据表明 USP13 去泛素化并稳定细胞周期蛋白 D1，从而促进 GC 中的细胞周期进程和细胞增殖。