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USP10 Inhibits Ferroptosis via Deubiquinating POLR2A in Head and Neck Squamous Cell Carcinoma
Diekuo Zhang1,2,3, Xueying Wang1,2,3, Shanhong Lu1,2,3
1Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Abstract:
Ferroptosis has become a new way to induce cell death in cancer therapy. Deubiquitinating enzymes (DUBs) contribute to cancer ferroptosis, but underlying mechanisms are not completely understood. Here, it is discovered that USP10 as a member of DUBs, is tightly associated with a poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Functionally, USP10 inhibits ferroptosis via transcriptionally upregulating the expression of SLC7A11 in HNSCC. Targeting USP10 via gene depletion and antagonist sensitizes HNSCC cells to ferroptosis inducers both in vitro and in vivo. Mechanistically, USP10 directly interacts with the largest RNA Polymerase II Subunit A (POLR2A), removes the K48- and K63-linked ubiquitin chains of POLR2A through its deubiquitinase activity and prevents ubiquitin-mediated degradation. Then, POLR2A transcriptionally activates SLC7A11, eventually leading to the suppression of ferroptosis. Overall, the study indicates that a novel USP10-POLR2A-SLC7A11 axis regulates ferroptosis, positioning USP10 as a potential therapeutic target in patients with HNSCC.
Insights
USP10, a deubiquitinating enzyme, promotes head and neck cancer by blocking ferroptosis. Targeting USP10 sensitizes cancer cells to ferroptosis inducers, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ferroptosis is an emerging cancer therapy strategy inducing cell death.
- Deubiquitinating enzymes (DUBs) influence cancer ferroptosis, but mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of USP10 in head and neck squamous cell carcinoma (HNSCC) ferroptosis.
- To elucidate the molecular mechanisms by which USP10 regulates ferroptosis in HNSCC.
Main Methods:
- Gene depletion and antagonist treatment in HNSCC cell lines and in vivo models.
- Co-immunoprecipitation assays to identify protein interactions.
- Western blotting and quantitative real-time PCR to assess protein and gene expression.
Main Results:
- USP10 expression correlates with poor prognosis in HNSCC patients.
- USP10 deubiquitinates POLR2A, stabilizing it and promoting SLC7A11 transcription.
- USP10 inhibition sensitizes HNSCC cells to ferroptosis inducers.
Conclusions:
- A novel USP10-POLR2A-SLC7A11 axis regulates ferroptosis in HNSCC.
- USP10 is a potential therapeutic target for enhancing ferroptosis-based cancer therapy in HNSCC.
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