USP10 Inhibits Ferroptosis via Deubiquinating POLR2A in Head and Neck Squamous Cell Carcinoma

Diekuo Zhang; Xueying Wang; Shanhong Lu; Yan Gao; Gangcai Zhu; Guo Li; Zongnan Yu; Junwei Hou; Helei Yan; Wenhui Yuan; Xin Zhang; Mien-Chie Hung; Zhifeng Liu; Yong Liu

doi:10.1002/advs.202412271

USP10 Inhibits Ferroptosis via Deubiquinating POLR2A in Head and Neck Squamous Cell Carcinoma

Adv Sci (Weinh). 2025 Jul 2:e12271. doi: 10.1002/advs.202412271. Online ahead of print.

Authors

Diekuo Zhang^{1

2

3}, Xueying Wang^{1

2

3}, Shanhong Lu^{1

2

3}, Yan Gao^{1

2

3}, Gangcai Zhu^{1

2

3}, Guo Li^{1

2

3}, Zongnan Yu^{1

2

3}, Junwei Hou^{1

4

5

6}, Helei Yan^{1

2

3}, Wenhui Yuan^{1

2

3}, Xin Zhang^{1

2

3

4}, Mien-Chie Hung^{7

8}, Zhifeng Liu^{1

2

3

9}, Yong Liu^{1

2

3

4}

Affiliations

¹ Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
² Otolaryngology Major Disease Research Key Laboratory of Hunan Province, 87 Xiangya Road, Changsha, Hunan, 410008, China.
³ Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province, Changsha, Hunan, 410008, China.
⁴ National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, 410008, China.
⁵ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁶ Center for Molecular Oncology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁷ Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan.
⁸ Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, 404328, Taiwan.
⁹ The First Affiliated Hospital, Department of Otorhinolaryngology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.

PMID: 40605431
DOI: 10.1002/advs.202412271

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.

Keywords: POLR2A; SLC7A11; USP10; ferroptosis; head and neck squamous cell carcinoma.

Abstract

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