Deacetylation of tumor-suppressor MST1 in Hippo pathway induces its degradation through HBXIP-elevated HDAC6 in promotion of breast cancer growth

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Abstract
Reduction or loss of tumor-suppressor mammalian STE20-like kinase 1 (MST1) in Hippo pathway contributes to the tumorigenesis. However, the mechanism leading to reduction of MST1 in cancers remains poorly understood. In this study, we explored the hypothesis that the oncoprotein hepatitis B X-interacting protein (HBXIP) is involved in the reduction of MST1 in breast cancer. Immunohistochemical analysis of tissue microarrays revealed that the expression of HBXIP was negatively associated with that of MST1 in 98 clinical breast tissue samples. Then we found that HBXIP could posttranslationally downregulate MST1 in breast cancer cells. Mechanistically, we identified that MST1 could be acetylated on its lysine 35 residue in the cells. Strikingly, the treatment with trichostatin A, an inhibitor of histone deacetylases (HDACs), markedly increased the levels of MST1 acetylation and protein in the cells. Interestingly, the oncoprotein HBXIP could significantly inhibit acetylation of MST1, resulting in the reduction of MST1 protein. Notably, we revealed that the HDAC6 could reduce the protein levels of MST1 through deacetylation modification of MST1 in the cells. Moreover, our data revealed that HBXIP upregulated HDAC6 at the levels of mRNA and protein by activating transcription factor nuclear factor-κB. Deacetylation of MST1 promoted the interaction of MST1 with HSC70 in the cells, resulting in a lysosome-dependent degradation of MST1 via chaperone-mediated autophagy (CMA). Functionally, the reduction of tumor-suppressor MST1 mediated by HBXIP promoted the growth of breast cancer cells in vitro and in vivo. Thus we conclude that the deacetylation of MST1 mediated by HBXIP-enhanced HDAC6 results in MST1 degradation in a CMA manner in promotion of breast cancer growth. Our finding provides new insights into the mechanism of tumor-suppressor MST1 reduction in breast cancer.

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