Involvement of EZH2 inhibition in lenalidomide and pomalidomide-mediated growth suppression in HTLV-1-infected cells
Involvement of EZH2 inhibition in lenalidomide and pomalidomide-mediated growth suppression in HTLV-1-infected cells
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DOI：
10.1016/j.bbrc.2021.08.051
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发表时间：
2021-08-26
影响因子：
3.1
通讯作者：
Kannagi，Mari
中科院分区：
文献类型：
--
作者：
Kondo，Nobuyo;Nagano，Yoshiko;Kannagi，Mari
免疫调节酰亚胺药物（IMiD），如来那度胺和泊马度胺，发挥多效性作用，例如，通过结合Cereblon蛋白并改变其底物特异性，在多发性骨髓瘤中发挥抗肿瘤作用。来那度胺被批准用于治疗由人T细胞白血病病毒1型（HTLV-1）引起的成人T细胞白血病/淋巴瘤（ATL），尽管其有效性的确切机制尚未完全阐明。在这里，我们使用HTLV-1感染的细胞系来研究IMiDs如何发挥抗ATL作用。在四种测试的HTLV-1感染细胞系中的三种中，用来那度胺或泊马度胺处理的细胞表现出轻度生长抑制而无细胞凋亡，这与IRF 4、c-Myc和磷酸化STAT 3水平降低以及SOCS 3表达增强相关。此外，在所有三种易感细胞系中，IMiD处理后zeste增强子同源物2（EZH 2）和三甲基组蛋白3 Lys 27（H3 K27 me 3）的水平降低。在多发性骨髓瘤细胞系中也观察到IMiD介导的EZH 2和H3 K27 me 3水平的降低。此外，用EZH 2抑制剂处理在HTLV-1感染的细胞和多发性骨髓瘤细胞中再现了IMiD介导的作用。这些发现有力地表明，EZH 2表达的减少涉及IMiD的抗肿瘤作用的机制。
Immunomodulatory imide drugs (IMiDs), such as lenalidomide and pomalidomide, exert pleiotropic effects, e.g., antitumor effects in multiple myeloma, by binding the protein Cereblon and altering its substrate specificity. Lenalidomide is approved for the treatment of adult T-cell leukemia/lymphoma (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1), although the precise mechanisms responsible for its effectiveness have not been fully elucidated. Here, we used HTLV-1-infected cell lines to investigate how IMiDs exert anti-ATL effects. In three of four tested HTLV-1-infected cell lines, the cells treated with lenalidomide or pomalidomide exhibited mild growth suppression without apoptosis, which was associated with decreased IRF4, c-Myc, and phosphorylated STAT3 levels as well as enhanced SOCS3 expression. Additionally, the levels of enhancer of zeste homolog 2 (EZH2) and trimethyl histone 3 Lys27 (H3K27me3) were decreased following IMiD treatment in all three susceptible cell lines. An IMiD-mediated reduction of EZH2 and H3K27me3 levels was also observed in a multiple myeloma cell line. Furthermore, treatment with an EZH2-inhibitor reproduced the IMiD-mediated effects in HTLV-1-infected cells and multiple myeloma cells. These findings strongly suggest that a reduction of EZH2 expression is involved in the mechanism underlying the antitumor effects of IMiD.