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