Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.
Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.
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DOI：
10.1038/s41420-020-00400-0
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发表时间：
2021-01-12
影响因子：
7
通讯作者：
Suzuki H
中科院分区：
文献类型：
--
作者：
Ishiguro K;Kitajima H;Niinuma T;Maruyama R;Nishiyama N;Ohtani H;Sudo G;Toyota M;Sasaki H;Yamamoto E;Kai M;Nakase H;Suzuki H
组蛋白修饰等表观遗传机制在多发性骨髓瘤（MM）的发病机制中起着关键作用。我们以前表明，EZH 2，一个组蛋白H3赖氨酸27（H3 K27）甲基转移酶，和G9，一个H3 K9甲基转移酶，是MM的潜在治疗靶点。此外，最近的研究表明，EZH 2和G9 a合作调节基因表达。因此，我们评估了MM中EZH 2和G9 a双重抑制的抗肿瘤作用。EZH 2抑制剂和G9 a抑制剂的组合通过诱导细胞周期停滞和细胞凋亡在体外强烈抑制MM细胞增殖。双重EZH 2/G9 a抑制也抑制体内MM细胞的异种移植物形成。在来自基因表达综合数据集的数据集中，较高的EZH 2和EHMT 2（编码G9 a）表达与MM患者中较差的预后显著相关。微阵列分析显示，EZH 2/G9 a抑制显著上调干扰素（IFN）刺激的基因，并抑制MM细胞中的IRF 4-MYC轴基因。值得注意的是，双重EZH 2/G9 a抑制降低了MM细胞中的H3 K27/H3 K9甲基化水平，并增加了内源性逆转录病毒（ERV）基因的表达，这表明ERV基因的激活可能诱导IFN应答。这些结果表明，EZH 2和G9 a的双重靶向可能是MM的有效治疗策略。
Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.
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影响因子：
64.5
作者：
Roulois D;Loo Yau H;Singhania R;Wang Y;Danesh A;Shen SY;Han H;Liang G;Jones PA;Pugh TJ;O'Brien C;De Carvalho DD
通讯作者：
De Carvalho DD
影响因子：
64.5
作者：
Chiappinelli KB;Strissel PL;Desrichard A;Li H;Henke C;Akman B;Hein A;Rote NS;Cope LM;Snyder A;Makarov V;Budhu S;Slamon DJ;Wolchok JD;Pardoll DM;Beckmann MW;Zahnow CA;Merghoub T;Chan TA;Baylin SB;Strick R
通讯作者：
Strick R
影响因子：
10.1
作者：
Ishiguro K;Kitajima H;Niinuma T;Ishida T;Maruyama R;Ikeda H;Hayashi T;Sasaki H;Wakasugi H;Nishiyama K;Shindo T;Yamamoto E;Kai M;Sasaki Y;Tokino T;Nakase H;Suzuki H
通讯作者：
Suzuki H
影响因子：
16
作者：
Mozzetta, Chiara;Pontis, Julien;Ait-Si-Ali, Slimane
通讯作者：
Ait-Si-Ali, Slimane