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LukS-PV Induces Apoptosis and Inhibits Proliferation Through Methyltransferase SET8 in Human Acute Myeloid Leukaemia Cells

Background: Histone modifiers contribute to leukaemia pathogenesis. LukS-PV is a component of the Panton-Valentine leukocidin (PVL) cytotoxin secreted by Staphylococcus aureus. We previously reported that LukS-PV induces apoptosis in human acute myeloid leukaemia (AML) cells (THP-1 and HL-60). However, it is unclear whether LukS-PV exerts biological effects through epigenetic regulation. We aimed to investigate the epigenetic regulatory mechanisms underlying the effects of LukS-PV. 
 
Methods: SET8 expression was quantified through reverse-transcription PCR and western blotting in patient-derived AML cells. To determine whether LukS-PV influences apoptosis and proliferation via SET8, AML cell lines HL-60 and NB-4 were treated with LukS-PV, and SET8 expression was quantified. Chromatin-immunoprecipitation (ChIP) was performed to determine whether LukS-PV regulates H4K20me1 via SET8, and transcriptional targets were determined through ChIP-seq and bioinformatic methods. 
 
Findings: Methyltransferase SET8 was upregulated in primary AML blasts and downregulated in LukS-PV-treated AML cells HL-60 and NB4. LukS-PV induced apoptosis and inhibited proliferation by downregulating SET8. Furthermore, LukS-PV regulated H4K20me1 through SET8. Genome-wide analysis identified PIK3CB as the direct target of LukS-PV-mediated H4K20me1. Furthermore, PIK3CB inhibitor GSK2636771 induced apoptosis and inhibited proliferation in HL-60 and NB4 cells. Moreover, LukS-PV induced apoptosis and inhibited proliferation in primary AML blasts. 
 
Conclusions: The present results indicate that LukS-PV induces apoptosis and inhibits proliferation in AML cells by downregulating SET8 and regulating downstream molecular targets, suggesting that SET8 is a potential target for AML therapy using LukS-PV for anti-leukaemia treatment. 
 
Funding Statement: This work was supported by the Anhui Natural Science Foundation(Grant No.1808085QH259), the Fundamental Research Funds for Central Universities (WK9110000107) and National Natural Science Foundation of China (Grant No.81572065). 
 
Declaration of Interests: The authors declare no conflict of interest. 
 
Ethics Approval Statement: This study was approved by the Ethics Committee and Institutional Review Board of University of Science and Technology of China, Anhui, China (Approval number: 2019-N(H)-101).