Toxin protein LukS-PV targeting complement receptor C5aR1 inhibits cell proliferation in hepatocellular carcinoma via the HDAC7-Wnt/β-catenin axis.

Hepatocellular carcinoma (HCC) is one of the common malignant tumors. Complement system has become a new focus of cancer research by changing the biological behavior of cancer cells to influence the growth of cancer. Recent studies reported that the complement C5a-C5aR1 axis can promote the malignant phenotype of multiple tumors through various signaling pathways. LukS-PV (Panton-Valentine), the S component of Staphylococcus aureus-secreted PV leucocidin, can also bind C5aR1 specifically. This project aims to investigate the role of LukS-PV on HCC cell proliferation and explore underlying molecular mechanisms. Our findings revealed that LukS-PV targeting C5aR1 inhibited HCC cell proliferation in vitro and in vivo. Interestingly, we discovered that LukS-PV inhibited the proliferation of HCC cells by upregulating the acetylation level of β-catenin to promote its protein degradation. In addition, histone deacetylase (HDAC)7 identified as a regulator mediates the deacetylation of β-catenin. Furthermore, our results showed that LukS-PV inhibited proliferation in HCC cells by downregulating HDAC7 to promote the degradation of β-catenin through ubiquitin-proteasome system. Collectively, our findings revealed that LukS-PV targeting C5aR1 inhibits HCC cell proliferation through the HDAC7-Wnt/β-catenin axis. These results revealing a novel mechanism that LukS-PV as a bacterial toxin inhibits HCC cell proliferation through epigenetic remodeling by targeting complement receptor C5aR1, suggest the strong potential of LukS-PV as a promising candidate for HCC treatment.