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

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.

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

“…Our results suggest that the second core part of Hippo signaling, MST2 protein, is neither involved in ccRCC progression nor in YAP1 regulation. Although MST1/2 kinases have been acknowledged as tumor-suppressor proteins since loss of function of MST1/2 was observed in prostate (46) and breast cancer (47), and a decreased MST1 mRNA level was associated with node metastasis in colorectal cancer (48), however, in hepatocellular carcinoma HepG2 cells increased MST1/2 levels were reported (49). Decreased MST1 expression was associated with promoter methylation of this gene in soft tissue sarcomas (50).…”

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…HDAC6 has two features that distinguish it from all the other HDACs: it is exclusively cytoplasmic and it has two catalytic domains (Gregoretti et al 2004). Initially described to be a specific alpha-tubulin deacetylase, HDAC6 was later found to deacetylate other substrates, including tau, heat-shock protein 90, the actin binding protein cortactin, the tumor suppressor macrophage stimulating 1 and the beta-catenin transcription factor Li et al 2008Li et al , 2016Kekatpure et al 2009;Cook et al 2014). Both the neuroprotective and neurotoxic effects of HDAC6 have been associated with altered acetylation of target proteins, not a result of histone acetylation and ensuing effects on chromatin (Table 1).…”

Oncogenic HBXIP enhances ZEB1 through Sp1 to accelerate breast cancer growth

“…Studies have shown that highly expressed HBXIP leads to the promotion of breast cancer development. 28,29 Herein, we evaluated the relationship between ZEB1 and HBXIP in regard to breast cancer malignancy. The levels of ZEB1 and HBXIP in clinical breast cancer samples were examined.…”