HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis  

作　　者：Lu Zhang Xiaolei Zhou Bowen Liu Xuhe Shi Xianmeng Li Feifei Xu Xueli Fu Xue Wang Kai Ye Tianzhi Jin Huimin Sun Qianqian Li Weiying Zhang Lihong Ye 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,Tianjin Key Laboratory of Protein Sciences,Department of Biochemistry and Molecular Biology,College of Life Sciences,Nankai University,Tianjin 300071,China [2]College of Food Science&Biology,Hebei University of Science and Technology,Shijiazhuang 050091,China [3]Henan Key Laboratory of Immunology and Targeted Drugs,School of Laboratory Medicine,Xinxiang Medical University,Xinxiang 453003,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第3期1053-1070,共18页药学学报（英文版）

基　　金：supported by the grants from National Natural Science Foundation of China(82072929,82072943,and 31870752,China).

摘　　要：Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.

关 键 词：Breast cancer metastasis Actomyosin cytoskeleton HBXIP Myosin-IIA NMHC-IIA PHOSPHORYLATION PKCβII BEZAFIBRATE 

分 类 号：R737.9[医药卫生—肿瘤]