FMRP protects breast cancer cells from ferroptosis by promoting SLC7A11 alternative splicing through interacting with hnRNPM
Nan Wang,
Bin Shi,
Lu Ding,
Xu Zhang,
Xiaolan Ma,
Songlin Guo,
Xia Qiao,
Libin Wang,
Duan Ma,
Jia Cao
Affiliations
Nan Wang
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China; Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, China
Bin Shi
Department of Emergency, General Hospital of Ningxia Medical University, Yinchuan, China
Lu Ding
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China
Xu Zhang
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China
Xiaolan Ma
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China; Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, China
Songlin Guo
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China
Xia Qiao
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China
Libin Wang
Department of Neurosurgery, Huazhong University of Science and Technology Union Shenzhen Hospital/Shenzhen Nanshan Hospital, Shenzhen, China; Corresponding author.
Duan Ma
Department of Biochemistry and Molecular Biology, Key Laboratory of Metabolism and Molecular Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China; Corresponding author.
Jia Cao
Department of Surgery Laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China; Corresponding author.
Ferroptosis is a unique modality of regulated cell death that is driven by iron-dependent phospholipid peroxidation. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. However, it remains elusive whether m6A reader Fragile X Mental Retardation Protein (FMRP) are involved in the modulation of ferroptosis in breast cancer (BC). In this study, we found that FMRP expression was elevated and associated with poor prognosis and pathological stage in BC patients. Overexpression of FMRP induced ferroptosis resistance and exerted oncogenic roles by positively regulating a critical ferroptosis defense gene SLC7A11. Mechanistically, upregulated FMRP catalyzes m6A modification of SLC7A11 mRNA and further influences the SLC7A11 translation through METTL3-dependent manner. Further studies revealed that FMRP interacts with splicing factor hnRNPM to recognize the splice site and then modulated the exon skip splicing event of SLC7A11 transcript. Interestingly, SLC7A11-S splicing variant can effectively promote FMRP overexpression-induced ferroptosis resistance in BC cells. Moreover, our clinical data suggested that FMRP/hnRNPM/SLC7A11 expression were significantly increased in the tumor tissues, and this signal axis was important evaluation factors closely related to the worse survival and prognosis of BC patients. Overall, our results uncovered a novel regulatory mechanism by which high FMRP expression protects BC cells from undergoing ferroptosis. Targeting the FMRP–SLC7A11 axis has a dual effect of inhibiting ferroptosis resistance and tumor growth, which could be a promising therapeutic target for treating BC.
