USP14 Positively Modulates Head and Neck Squamous Carcinoma Tumorigenesis and Potentiates Heat Shock Pathway through HSF1 Stabilization

SIMPLE SUMMARY: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with a heterogeneous characteristic. We firstly systematically screened the critical gene ubiquitin-specific protease 14 (USP14) in HNSCC from the DUB library after building a risk signature. Our data suggested that USP14 regulated heat shock transcription factor 1 (HSF1) stabilization by its deubiquitination and increased its downstream proteins, such as heat shock protein 60 (HSP60), HSP70, and HSP90, to promote HNSCC proliferation and lung metastasis in vivo and in vitro, and the overexpression of HSF1 reversed the inhibitory effect of USP14 depletion in vivo. Forty-five tissue samples from patients with HNSCC cancer were collected to determine the correlation of USP14 and HSF1 expression in the diagnosis of HNSCC, which is a novel mechanism of USP14 as a carcinogenic gene in HNSCC. Our results emphasized that USP14 and its downstream HSF1 have therapeutic potential in targeting HNSCC. ABSTRACT: 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.