S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells.
S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells.
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DOI：
10.1097/cad.0000000000000166
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发表时间：
2015-02
影响因子：
2.3
通讯作者：
Yang PM
中科院分区：
文献类型：
--
作者：
Liu TP;Lo HL;Wei LS;Hsiao HH;Yang PM
zeste增强子同源物2（EZH 2）已成为一种新的抗癌靶点。近年来已经开发了各种EZH 2抑制剂。其中，已知3-去氮普兰诺菌素A（DZNep）通过间接途径消耗EZH 2蛋白表达。相反，GSK 343通过S-腺苷-L-甲硫氨酸竞争性途径直接抑制酶活性。因此，我们提出DZNep和GSK 343可能对癌细胞发挥不同的作用。在这项研究中，我们发现GSK 343而不是DZNep诱导癌细胞的自噬细胞死亡。GSK 343诱导的自噬不需要抑制EZH 2表达。此外，GSK 343增强了多激酶抑制剂索拉非尼在人肝细胞癌细胞中的抗癌活性。我们的研究结果表明，GSK 343是一种比DZNep更有效的抗癌剂，并且我们首次表明它可以作为自噬诱导剂。
The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-l-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.