LukS-PV Induces Apoptosis via the SET8-H4K20me1-PIK3CB Axis in Human Acute Myeloid Leukemia Cells.
LukS-PV Induces Apoptosis via the SET8-H4K20me1-PIK3CB Axis in Human Acute Myeloid Leukemia Cells.
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Luks-PV通过人类急性髓样白血病细胞中的SET8-H4K20ME1-PIK3CB轴诱导凋亡。
DOI：
10.3389/fonc.2021.718791
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发表时间：
2021
影响因子：
4.7
通讯作者：
Ma XL
中科院分区：
文献类型：
--
作者：
Xu LF;Shi L;Zhang SS;Ding PS;Ma F;Song KD;Qiang P;Chang WJ;Dai YY;Mei Y;Ma XL
有证据表明，组蛋白修饰障碍参与白血病的发病机制。我们以前报道过，LukS-PV，Panton-Valentine leukocidin（PVL）的一个组成部分，具有抗白血病活性，可以诱导分化，增加凋亡，抑制急性髓性白血病（AML）细胞的增殖。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剂发挥抗白血病活性。在这项研究中，结果表明，LukS-PV通过下调甲基转移酶SET 8及其靶向组蛋白H4在Lys 20处单甲基化（H4 K20 me 1）诱导凋亡。此外，染色质免疫沉淀测序和聚合酶链反应鉴定了激酶PIK 3CB作为由SET 8/H4 K20 me 1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SET 8的PIK 3CB-AKT-FOXO 1信号通路诱导细胞凋亡。这项研究表明，SET 8下调是LukS-PV诱导AML细胞凋亡的机制之一，表明SET 8可能是AML的潜在治疗靶点。此外，LukS-PV可能是治疗靶向表观遗传修饰的AML的候选药物。
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 PIK3CB as a downstream target gene for apoptosis mediated by SET8/H4K20me1. Finally, our results indicated that LukS-PV induced apoptosis via 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.
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