USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
Anti-estrogen endocrine therapies greatly improve survival of estrogen receptor positive (ER + ) breast cancer. Unfortunately, about 30% of patients do not respond to endocrine therapies initially. We previously showed that deubiquitinase USP35 and ERα act in a positive feedback loop to promote the carcinogenesis of ER+ breast cancer although it is unclear whether USP35 regulates cell death in ER+ breast cancer. In this study, we uncovered that USP35 inhibited ferroptosis of ER+ breast cancer cells. Mechanistically, USP35 interacted with, deubiquitinated, and stabilized BRD4. Consequentially, BRD4 mediated USP35-induced SLC7A11 upregulation, inhibiting ferroptosis and promoting the growth of ER+ breast cancer cells. Furthermore, BRD4 inhibitor (+)-JQ-1 inhibited USP35-enhanced tumorigenesis in vivo. Our findings demonstrated that the USP35-BRD4-SLC7A11 axis contributes to the growth of ER+ breast cancer by inhibiting ferroptosis. Targeting USP35 together with ferroptosis inducer may represent a potential promising strategy for treating ER+ breast cancer that does not respond to endocrine therapies.
Authors
- Zewei Jiang
- Haihua Gu (ORCID: https://orcid.org/0000-0003-2154-9900)
- Changrui Qian (ORCID: https://orcid.org/0000-0001-8963-1260)
- Guang Wu (ORCID: https://orcid.org/0000-0002-6162-500X)
- Tao Wu (ORCID: https://orcid.org/0000-0002-9916-4253)
- Rixu Lin (ORCID: https://orcid.org/0000-0003-2498-8116)
- Tong Zhou (ORCID: https://orcid.org/0000-0003-1872-806X)
- Jiawei Yu (ORCID: https://orcid.org/0000-0002-7973-1695)
- Jiawei Cao (ORCID: https://orcid.org/0000-0001-6268-5912)
- Licai He (ORCID: https://orcid.org/0000-0002-1607-5619)
- Junqiang Wang (ORCID: https://orcid.org/0000-0001-5244-6483)
- Yi Ren (ORCID: https://orcid.org/0000-0003-2218-9935)
- Hongzhi Li (ORCID: https://orcid.org/0009-0002-9962-6814)
- Min Liu (ORCID: https://orcid.org/0000-0002-3280-472X)
Institutions
- Wenzhou Medical University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Ruian People's Hospital (CN)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1038/s42003-025-07513-1
- Citations
- 8
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 12.15
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- Sun Yat-sen University
- Wenzhou Municipal Science and Technology Bureau
- Key Discipline of Zhejiang Province in Medical Technology
- Natural Science Foundation of Zhejiang Province