2. Academic Validation
  3. HBXIP blocks myosin-IIA assembly by phosphorylating and interacting with NMHC-IIA in breast cancer metastasis

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

  • Acta Pharm Sin B. 2023 Mar;13(3):1053-1070. doi: 10.1016/j.apsb.2022.11.025.
Lu Zhang 1,  Xiaolei Zhou 2,  Bowen Liu 3,  Xuhe Shi 1,  Xianmeng Li 1,  Feifei Xu 1,  Xueli Fu 1,  Xue Wang 1,  Kai Ye 1,  Tianzhi Jin 1,  Huimin Sun 1,  Qianqian Li 1,  Weiying Zhang 1,  Lihong Ye 1
Affiliations

Affiliations

  • 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.
PMID: 36970214 DOI: 10.1016/j.apsb.2022.11.025
Abstract

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.

Keywords

Actomyosin cytoskeleton; Bezafibrate; Breast cancer metastasis; HBXIP; Myosin-IIA; NMHC-IIA; PKCβII; Phosphorylation.

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