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 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

作者机构：State Key Laboratory of Medicinal Chemical BiologyTianjin Key Laboratory of Protein SciencesDepartment of Biochemistry and Molecular BiologyCollege of Life SciencesNankai UniversityTianjin 300071China College of Food Science&BiologyHebei University of Science and TechnologyShijiazhuang 050091China Henan Key Laboratory of Immunology and Targeted DrugsSchool of Laboratory MedicineXinxiang Medical UniversityXinxiang 453003China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第3期

页      面：1053-1070页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

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

主　　题：Breast cancer metastasis Actomyosin cytoskeleton HBXIP Myosin-IIA NMHC-IIA Phosphorylation PKCβII Bezafibrate 

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.