E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma
Abstract Background Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related mortality worldwide due to its high aggressive potential and drug resistance. Previous studies have revealed an important function of HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (H...
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2025-03-01
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| Online Access: | https://doi.org/10.1186/s13062-025-00622-1 |
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| author | Xu Zhang Fayu Liu Qigen Fang Changfu Sun Jie Fan |
| author_facet | Xu Zhang Fayu Liu Qigen Fang Changfu Sun Jie Fan |
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| description | Abstract Background Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related mortality worldwide due to its high aggressive potential and drug resistance. Previous studies have revealed an important function of HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (HERC5) in cancer. Six GEO gene microarrays identified HERC5 as a significant upregulated gene in OSCC tissues or cells (log2 Fold change > 1 and adj.p < 0.05). This study aimed to explore the role and underlying mechanisms of HERC5 in OSCC development. Results High HERC5 expression in OSCC tissues was confirmed by our hospital validation cohort and positively correlated with primary tumor stages. Subsequent functional studies demonstrated that knockdown of HERC5 inhibited the migratory and invasive capabilities with decrease of Vimentin and increase of E-cadherin in OSCC cells. In cisplatin treatment, cell survival rates were significantly reduced in HERC5-silencing OSCC cells, accompanied by the increase in cytotoxicity, DNA damage and apoptosis. OSCC cell-derived tumor xenograft displayed that HERC5 depletion inhibited pulmonary metastasis as well as restored the cisplatin-induced tumor burden. In line with this, overexpression of HERC5 yielded the opposite alterations both in vivo and in vitro. Mechanistically, UDP-glucose 6-dehydrogenase (UGDH) was identified as a HERC5-binding protein. Cysteine residue at position 994 in the HECT domain of HERC5 catalyzed the conjugation of ubiquitin-like protein Interferon-induced 15 kDa protein (ISG15) to UGDH (ISGylation of UGDH) and facilitated its phosphorylation, therefore enhancing SNAI1 mRNA stability. SNAI1 depletion inhibited HERC5 overexpression-triggered invasion and cisplatin resistance of OSCC cells. Conclusions Our study indicates that HERC5 may be a promising therapeutic target for OSCC. |
| format | Article |
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| language | English |
| publishDate | 2025-03-01 |
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| series | Biology Direct |
| spelling | doaj-art-3ebe046a669245be99681bee30c6a2a62025-08-20T01:57:47ZengBMCBiology Direct1745-61502025-03-0120111610.1186/s13062-025-00622-1E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinomaXu Zhang0Fayu Liu1Qigen Fang2Changfu Sun3Jie Fan4Department of Head Neck and Thyroid, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalDepartment of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, Liaoning Province Key Laboratory of Oral Disease, China Medical UniversityDepartment of Head Neck and Thyroid, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalDepartment of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, Liaoning Province Key Laboratory of Oral Disease, China Medical UniversityDepartment of Head Neck and Thyroid, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalAbstract Background Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related mortality worldwide due to its high aggressive potential and drug resistance. Previous studies have revealed an important function of HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (HERC5) in cancer. Six GEO gene microarrays identified HERC5 as a significant upregulated gene in OSCC tissues or cells (log2 Fold change > 1 and adj.p < 0.05). This study aimed to explore the role and underlying mechanisms of HERC5 in OSCC development. Results High HERC5 expression in OSCC tissues was confirmed by our hospital validation cohort and positively correlated with primary tumor stages. Subsequent functional studies demonstrated that knockdown of HERC5 inhibited the migratory and invasive capabilities with decrease of Vimentin and increase of E-cadherin in OSCC cells. In cisplatin treatment, cell survival rates were significantly reduced in HERC5-silencing OSCC cells, accompanied by the increase in cytotoxicity, DNA damage and apoptosis. OSCC cell-derived tumor xenograft displayed that HERC5 depletion inhibited pulmonary metastasis as well as restored the cisplatin-induced tumor burden. In line with this, overexpression of HERC5 yielded the opposite alterations both in vivo and in vitro. Mechanistically, UDP-glucose 6-dehydrogenase (UGDH) was identified as a HERC5-binding protein. Cysteine residue at position 994 in the HECT domain of HERC5 catalyzed the conjugation of ubiquitin-like protein Interferon-induced 15 kDa protein (ISG15) to UGDH (ISGylation of UGDH) and facilitated its phosphorylation, therefore enhancing SNAI1 mRNA stability. SNAI1 depletion inhibited HERC5 overexpression-triggered invasion and cisplatin resistance of OSCC cells. Conclusions Our study indicates that HERC5 may be a promising therapeutic target for OSCC.https://doi.org/10.1186/s13062-025-00622-1HERC5Oral squamous cell carcinomaMetastasisCisplatin sensitivityISGylationUGDH |
| spellingShingle | Xu Zhang Fayu Liu Qigen Fang Changfu Sun Jie Fan E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma Biology Direct HERC5 Oral squamous cell carcinoma Metastasis Cisplatin sensitivity ISGylation UGDH |
| title | E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma |
| title_full | E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma |
| title_fullStr | E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma |
| title_full_unstemmed | E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma |
| title_short | E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma |
| title_sort | e3 ligase herc5 catalyzed ugdh isgylation promotes snai1 mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma |
| topic | HERC5 Oral squamous cell carcinoma Metastasis Cisplatin sensitivity ISGylation UGDH |
| url | https://doi.org/10.1186/s13062-025-00622-1 |
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