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

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 pro...

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Main Authors: Jiawei Cao, Tao Wu, Tong Zhou, Zewei Jiang, Yinrui Ren, Jiawei Yu, Jiayi Wang, Changrui Qian, Guang Wu, Licai He, Hongzhi Li, Rixu Lin, Min Liu, Haihua Gu
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-025-07513-1
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author Jiawei Cao
Tao Wu
Tong Zhou
Zewei Jiang
Yinrui Ren
Jiawei Yu
Jiayi Wang
Changrui Qian
Guang Wu
Licai He
Hongzhi Li
Rixu Lin
Min Liu
Haihua Gu
author_facet Jiawei Cao
Tao Wu
Tong Zhou
Zewei Jiang
Yinrui Ren
Jiawei Yu
Jiayi Wang
Changrui Qian
Guang Wu
Licai He
Hongzhi Li
Rixu Lin
Min Liu
Haihua Gu
author_sort Jiawei Cao
collection DOAJ
description 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.
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spelling doaj-art-be3cda298e084d189bc8a19edd16c93a2025-01-19T12:35:19ZengNature PortfolioCommunications Biology2399-36422025-01-018111310.1038/s42003-025-07513-1USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axisJiawei Cao0Tao Wu1Tong Zhou2Zewei Jiang3Yinrui Ren4Jiawei Yu5Jiayi Wang6Changrui Qian7Guang Wu8Licai He9Hongzhi Li10Rixu Lin11Min Liu12Haihua Gu13Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Pathology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Orthopedics, Third Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityAbstract 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.https://doi.org/10.1038/s42003-025-07513-1
spellingShingle Jiawei Cao
Tao Wu
Tong Zhou
Zewei Jiang
Yinrui Ren
Jiawei Yu
Jiayi Wang
Changrui Qian
Guang Wu
Licai He
Hongzhi Li
Rixu Lin
Min Liu
Haihua Gu
USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
Communications Biology
title USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
title_full USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
title_fullStr USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
title_full_unstemmed USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
title_short USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis
title_sort usp35 promotes the growth of er positive breast cancer by inhibiting ferroptosis via brd4 slc7a11 axis
url https://doi.org/10.1038/s42003-025-07513-1
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