The ubiquitin-proteasome system is a pivotal intracellular proteolysis process in posttranslational modification. It regulates multiple cellular processes. Deubiquitinating enzymes (DUBs) are a stabilizer in proteins associated with tumor growth and metastasis. However, the link between DUBs and HNSCC remains incompletely understood. In this study, therefore, we identified USP14 as a tumor proliferation enhancer and a substantially hyperactive deubiquitinase in HNSCC samples, implying a poor prognosis prediction. Silencing USP14 in vitro conspicuously inhibited HNSCC cell proliferation and migration. Consistently, defective USP14 in vivo significantly diminished HNSCC tumor growth and lung metastasis compared to the control group. Luciferase assays indicated that HSF1 was downstream from USP14, and an evaluation of the cellular effects of HSF1 overexpression in USP14-dificient mice tumors showed that elevated HSF1 reversed HNSCC growth and metastasis predominantly through the HSF1-HSP pathway. Mechanistically, USP14 encouraged HSF1 expression by deubiquitinating and stabilizing HSF1, which subsequently orchestrated transcriptional activation in HSP60, HSP70, and HSP90, ultimately leading to HNSCC progression and metastasis. Collectively, we uncovered that hyperactive USP14 contributed to HNSCC tumor growth and lung metastasis by reinforcing HSF1-depedent HSP activation, and our findings provided the insight that targeting USP14 could be a promising prognostic and therapeutic strategy for HSNCC.
泛素-蛋白酶体系统是翻译后修饰中关键的细胞内蛋白降解途径，调控多种细胞进程。去泛素化酶作为肿瘤生长与转移相关蛋白的稳定因子，但其与头颈部鳞状细胞癌的关联尚未完全阐明。本研究通过分析临床样本发现USP14在头颈部鳞状细胞癌中呈现显著高活性，可作为肿瘤增殖促进因子及不良预后预测指标。体外实验表明沉默USP14能显著抑制头颈部鳞状细胞癌细胞的增殖与迁移能力。动物实验进一步证实，与对照组相比，USP14缺陷可明显抑制头颈部鳞状细胞癌的肿瘤生长和肺转移。荧光素酶报告基因检测显示HSF1位于USP14下游，在USP14缺陷小鼠肿瘤中过表达HSF1的细胞效应评估表明，升高的HSF1主要通过HSF1-HSP通路逆转头颈部鳞状细胞癌的生长与转移。机制研究发现，USP14通过去泛素化修饰稳定HSF1蛋白，进而促进HSP60、HSP70和HSP90的转录激活，最终驱动头颈部鳞状细胞癌进展与转移。本研究揭示高活性USP14通过增强HSF1依赖的HSP通路激活促进头颈部鳞状细胞癌生长及肺转移，为靶向USP14作为头颈部鳞状细胞癌潜在预后标志和治疗策略提供了理论依据。
肿瘤(癌症)患者之家