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

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.

 

Comments：

The passage describes a study that investigates the regulatory mechanism of non-muscle myosin-IIA disassembly in tumor metastasis, particularly in breast cancer. The researchers found that the oncoprotein HBXIP promotes breast cancer cell migration by blocking myosin-IIA assembly. They identified that HBXIP directly interacts with the assembly-competent domain of non-muscle heavy chain myosin-IIA (NMHC-IIA) and enhances its interaction with PKCβII, a protein kinase that phosphorylates NMHC-IIA at S1916. The researchers also discovered that HBXIP induces the transcription of PRKCB, the gene that encodes PKCβII, by coactivating Sp1 and triggers PKCβII kinase activity. Furthermore, the study showed that the anti-hyperlipidemic drug bezafibrate (BZF) suppresses breast cancer metastasis by inhibiting PKCβII-mediated NMHC-IIA phosphorylation both in vitro and in vivo.

In summary, the study sheds light on the role of HBXIP in promoting myosin-IIA disassembly in breast cancer cell migration and invasion. It also identifies the molecular mechanism by which HBXIP regulates NMHC-IIA phosphorylation and highlights the potential of BZF as an effective anti-metastatic drug in breast cancer.

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