E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related mortality worldwide, primarily due to its aggressive nature and resistance to treatment. Emerging evidence highlights the role of HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (HERC5) in cancer progression. Analysis of six GEO gene microarrays identified HERC5 as significantly upregulated in OSCC tissues and cells (log2 fold change > 1, adj. p < 0.05). This study investigates the role of HERC5 in OSCC development and the underlying molecular mechanisms.
Results: Validation using our hospital cohort confirmed elevated HERC5 expression in OSCC tissues, which correlated positively with primary tumor stage. Functional assays demonstrated that HERC5 knockdown suppressed OSCC cell migration and invasion, accompanied by decreased Vimentin and increased E-cadherin expression. Furthermore, silencing HERC5 VH298 enhanced cisplatin sensitivity, reducing cell survival while increasing cytotoxicity, DNA damage, and apoptosis. In a tumor xenograft model, HERC5 depletion inhibited pulmonary metastasis and restored cisplatin-induced tumor suppression. Conversely, HERC5 overexpression produced opposite effects both in vitro and in vivo. Mechanistically, UDP-glucose 6-dehydrogenase (UGDH) was identified as a direct binding partner of HERC5. The cysteine residue at position 994 in the HECT domain of HERC5 catalyzed the ISGylation of UGDH (attachment of the ubiquitin-like protein ISG15), promoting its phosphorylation and enhancing SNAI1 mRNA stability. Notably, SNAI1 depletion reversed HERC5-induced invasion and cisplatin resistance in OSCC cells.
Conclusions: These findings suggest that HERC5 plays a pivotal role in OSCC progression and chemoresistance, highlighting its potential as a therapeutic target.