Xu Liang Fei, Shi Lan, Zhang Shan Shan, Ding Peng Sheng, Ma Fan, Song Kai Di, Qiang Ping, Chang Wen Jiao, Dai Yuan Yuan, Mei Yi De, Ma Xiao Ling
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
University of Science and Technology of China, School of Life Sciences and Medicine, USTC Life Sciences, Hefei, China.
Front Oncol. 2021 Oct 20;11:718791. doi: 10.3389/fonc.2021.718791. eCollection 2021.
Evidence suggests that histone modification disorders are involved in leukemia pathogenesis. We previously reported that LukS-PV, a component of Panton-Valentine leukocidin (PVL), has antileukemia activities that can induce differentiation, increase apoptosis, and inhibit proliferation of acute myeloid leukemia (AML) cells. Furthermore, LukS-PV inhibited hepatoma progression by regulating histone deacetylation, speculating that LukS-PV may exert antileukemia activity by targeting histone modification regulators. In this study, the results showed that LukS-PV induced apoptosis by downregulating the methyltransferase SET8 and its target histone H4 monomethylated at Lys 20 (H4K20me1). Furthermore, chromatin immunoprecipitation sequencing and polymerase chain reaction identified the kinase as a downstream target gene for apoptosis mediated by SET8/H4K20me1. Finally, our results indicated that LukS-PV induced apoptosis the PIK3CB-AKT-FOXO1 signaling pathway by targeting SET8. This study indicates that SET8 downregulation is one of the mechanisms by which LukS-PV induces apoptosis in AML cells, suggesting that SET8 may be a potential therapeutic target for AML. Furthermore, LukS-PV may be a drug candidate for the treatment of AML that targets epigenetic modifications.
有证据表明组蛋白修饰紊乱与白血病发病机制有关。我们之前报道过，杀白细胞素（PVL）的一个组分LukS-PV具有抗白血病活性，可诱导急性髓系白血病（AML）细胞分化、增加凋亡并抑制其增殖。此外，LukS-PV通过调节组蛋白去乙酰化抑制肝癌进展，推测LukS-PV可能通过靶向组蛋白修饰调节因子发挥抗白血病活性。在本研究中，结果显示LukS-PV通过下调甲基转移酶SET8及其靶标赖氨酸20单甲基化的组蛋白H4（H4K20me1）诱导凋亡。此外，染色质免疫沉淀测序和聚合酶链反应确定激酶 是由SET8/H4K20me1介导的凋亡的下游靶基因。最后，我们的结果表明LukS-PV通过靶向SET8诱导PIK3CB-AKT-FOXO1信号通路凋亡。本研究表明SET8下调是LukS-PV诱导AML细胞凋亡的机制之一，提示SET8可能是AML的一个潜在治疗靶点。此外，LukS-PV可能是一种针对表观遗传修饰治疗AML的候选药物。
