Ubiquitin-specific protease 4 (USP4) represents a potential oncogene involved in various human cancers. Nevertheless, the biological roles and precise mechanism of USP4 in esophageal squamous cell carcinoma (ESCC) progression are not understood. Here, USP4 expression was found to be markedly upregulated in ESCC tumor tissues and cells. Loss- and gain-of-function assays suggested that USP4 silencing inhibited ESCC cell proliferation, migration, and invasion, while USP4 overexpression promoted these behaviors. Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo. As a target molecule of USP4, transforming growth factor-β-activated kinase 1 (TAK1) also showed high expression in ESCC. Moreover, we observed that USP4 specifically interacted with TAK1 and stabilized TAK1 protein levels via deubiquitination in ESCC cells. Importantly, USP4 promotes ESCC proliferation, migration, and invasion via the MEK/ERK signaling pathway and can be inhibited by U0126. Neutral red (NR), an inhibitor of USP4 can suppress ESCC progression in vitro and in vivo. Overall, this study revealed that USP4/TAK1 plays crucial roles in ESCC progression by modulating proliferation, migration, and invasion, and USP4 might be a potential therapeutic target in ESCC.

泛素特异性蛋白酶 4 (USP4) 是一种与多种人类癌症相关的潜在癌基因。然而，USP4 在食管鳞状细胞癌 (ESCC) 进展中的生物学作用和精确机制尚不清楚。在这里，发现 USP4 表达在 ESCC 肿瘤组织和细胞中显着上调。功能丧失和获得检测表明，USP4 沉默抑制 ESCC 细胞增殖、迁移和侵袭，而 USP4 过表达则促进这些行为。一致地，USP4沉默抑制体内ESCC裸鼠模型中的肿瘤生长和转移。作为USP4的靶分子，转化生长因子-β激活激酶1（TAK1）在食管鳞癌中也表现出高表达。此外，我们观察到 USP4 与 TAK1 特异性相互作用，并通过 ESCC 细胞中的去泛素化稳定 TAK1 蛋白水平。重要的是，USP4 通过 MEK/ERK 信号通路促进 ESCC 增殖、迁移和侵袭，并且可以被 U0126 抑制。中性红 (NR) 是 USP4 的抑制剂，可以在体外和体内抑制食管鳞癌的进展。总体而言，本研究表明 USP4/TAK1 通过调节增殖、迁移和侵袭在 ESCC 进展中发挥关键作用，USP4 可能是 ESCC 的潜在治疗靶点。