USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis

作者：Jiawei Cao, Tao Wu, Tong Zhou, Zewei Jiang, Yi Ren, Jiawei Yu, Jiayi Wang, Changrui Qian, Guang Wu, Licai He, Hongzhi Li, Rixu Lin, Min Liu, Haihua Gu · 发表于：Communications Biology · 年份：2025 · DOI：10.1038/s42003-025-07513-1 · 被引用次数：12 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、Cancer-related gene regulation

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. USP35 regulates ferroptosis in ER+ breast cancer. USP35 interacts with, deubiquitinates, and stabilizes BRD4, which mediates USP35-induced upregulation of SLC7A11. This process inhibits ferroptosis and promotes the growth of ER+ breast cancer cells.