gp78-regulated KAP1 phosphorylation induces radioresistance in breast cancer by facilitating PPP1CC/PPP2CA ubiquitination
Yamei Han,
Mingming Xiao,
Shaorong Zhao,
Han Wang,
Rui Li,
Bo Xu
Affiliations
Yamei Han
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China; Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Mingming Xiao
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Shaorong Zhao
Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Han Wang
Center for Intelligent Oncology, Chongqing University Cancer Hospital, Chongqing University School of Medicine, Chongqing 400030, China
Rui Li
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China; Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Bo Xu
Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China; Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Center for Intelligent Oncology, Chongqing University Cancer Hospital, Chongqing University School of Medicine, Chongqing 400030, China; Corresponding author
Summary: Adjuvant radiation therapy is a common treatment for breast cancer, yet its effectiveness is often limited by radioresistance in patients. Identifying novel targets to combat this radioresistance is imperative. Recent investigations show that gp78 is upregulated in drug-resistant breast cancer cells. Our study reveals that gp78 markedly increased the phosphorylation of KAP1 and promoted DNA damage repair caused by ionizing radiation. Mechanistically, gp78 degrades phosphatases (PPP1CC/PPP2CA) in a ubiquitination-dependent manner. PPP1CC and PPP2CA are crucial regulators of KAP1 phosphorylation in response to DNA damage. Therefore, gp78 leads to a notable elevation in the phosphorylation of KAP1 by degrading phosphatases, thereby promoting the DNA damage repair process and increasing the radioresistance of tumor cells. The identification of gp78 as a pivotal regulator in radioresistance suggests a promising avenue for intervention. Combining blockade strategies targeting gp78 holds a signification potential for reversing radioresistance and improving the efficacy of breast cancer radiotherapy.
