Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 2:e12271.
doi: 10.1002/advs.202412271. Online ahead of print.

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

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

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

Diekuo Zhang et al. Adv Sci (Weinh). .

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.

PubMed Disclaimer

References

    1. R. L. Siegel, K. D. Miller, N. S. Wagle, A. Jemal, CA Cancer J. Clin. 2023, 73, 17.
    1. M. D. Mody, J. W. Rocco, S. S. Yom, R. I. Haddad, N. F. Saba, Lancet 2021, 398, 2289.
    1. S. J. Dixon, K. M. Lemberg, M. R. Lamprecht, R. Skouta, E. M. Zaitsev, C. E. Gleason, D. N. Patel, A. J. Bauer, A. M. Cantley, W. S. Yang, B. Morrison 3rd, B. R. Stockwell, Cell 2012, 149, 1060.
    1. A. Ghoochani, E. C. Hsu, M. Aslan, M. A. Rice, H. M. Nguyen, J. D. Brooks, E. Corey, R. Paulmurugan, T. Stoyanova, Cancer Res. 2021, 81, 1583.
    1. J. P. Friedmann Angeli, D. V. Krysko, M. Conrad, Nat. Rev. Cancer 2019, 19, 405.